Demystifying Regulatory Affairs and HTA┃Anke-Peggy Holtorf

On this episode, Dr. Anke-Peggy Holtorf joins us to help demystify the complex processes of regulatory affairs and health technology assessment (HTA) and explain the crucial role of patients in these processes.

Anke acts as Secretary of the Board at Health Technology Assessment international  and is a Steering Committee member and project coordinator for the Patient and Citizen Involvement in HTA Interest Group. She is co-editor of the 2nd edition of the book on Patient Involvement in HTA, which will be published in 2025. Anke has also taught graduate courses in International Health Policy, HTA, and the role of patient involvement.

Anke's global experience and depth of knowledge spanning decades shine through as she simplifies some highly technical and complex concepts for our listeners. 

Chapters:
0:00 - Introductions
1:34 - Overview of regulatory affairs and HTA
6:48 - The regulatory approval process
12:09 - Patient involvement in regulatory affairs
22:19 - Overcoming barriers to patient involvement
27:32 - Regulatory success rates
30:30 - The HTA process
32:32 - Differences in healthcare models
36:46 - Factors evaluated in HTA
43:45 - Patient involvement in HTA
54:32 - Advice for patients and stakeholders
59:08 - Reflections with Caitlin and Clarinda

Resources and definitions:

• HTA - Health Technology Assessment 
• Reimbursement: the process by which healthcare providers are compensated/paid back for the medical services they provide, either by the government or through insurance
• Out-of-pocket costs: when patients pay for their own medical costs
• FDA - US Food and Drug Administration
• EMA - European Medicines Agency
• Chinese FDA 
• QALY - Quality adjusted life years
• WHO - World Health Organization
• NICE - National Institute for Health and Care Excellence, UK
• CF Trust - Cystic Fibrosis Trust 
• EUPATI - European Patients' Academy on Therapeutic Innovation 
• EUCAPA - European Capacity Building for Patients 
• Anke's report on Patient Involvement in HTA in Europe - full report and short version

Have feedback or suggestions for us? We'd love to hear from you!
Website: notjustpatients.com
LinkedIn: Not Just Patients
Email: info@notjustpatients.com

Transcript

Anke
00:00:00
I mean, the question is, why do we have healthcare systems anyway? Why don't we leave it up to the people to care for their health? 

Clarinda
00:00:10
Hi, I'm Caitlin and I'm Clarinda. And this is Not Just Patients, a podcast where we break barriers to meaningful patient involvement in health care. Thanks so much for tuning in. Our guest today is Dr. Anke-Peggy Holtorf, who will be helping us demystify regulatory affairs. Anke's areas of expertise include the value of healthcare products and policy decisions related to health technologies, health technology assessment processes, outcomes research and health economics with global experience, including in low and middle income countries. She has published broadly on various subjects such as evidence based decision making, policies in health care, and the methods for including the patient perspective at Health Technology Assessment International. She acts as Secretary of the board and is a steering committee member and project coordinator for the patient and citizen involvement in HDA. Interest group, where she has co-led several projects.

Clarinda
00:01:07
She's co-editor of the second edition of the book on patient involvement in HDA, which will be published in 2025. In addition, as a guest lecturer and adjunct faculty at the University of Utah, Anka has taught graduate courses in international health policy, including HTA and the Role of Patient Involvement. It's a real pleasure to have you here today. Thank you so much for joining us.

Anke
00:01:31
It's a pleasure to be here. Thanks for inviting me.

Clarinda
00:01:34
Before we jump in, I would like to set the context for our listeners. So by and large, I think that a lot of people know that medicines go through clinical trials, but they don't necessarily know what happens between the clinical trial and the time that they get the medicine in their hand. So that's where these processes come in. And maybe we can just start with you helping us define regulatory affairs and HDR and positioning them on the entire timeline of medicine development. Yeah.

Anke
00:02:04
I'll try to do that. As you just pointed out, medicines are developed in a quite structured way usually, and then at some point they're ready for the market.

Anke
00:02:15
And here is where regulatory processes set in, because we only want the products which are good for us in a way. And so the first question which is asked by the regulatory authorities is does this product do more good than harm for patients? So basically they look at all the information they have, which is information which comes from the clinical trials. And based on the information from these studies, they will assess the clinical benefits that come from these products and the potential safety issues which can be expected After evaluating that, if they say, okay, this product definitely does more good than harm, then they give the market authorization, which means that a product can come to the market. But there is an additional hurdle they have to overcome to get reimbursement, because if they don't get reimbursement from whatever system the country has, people will have to pay out of pocket for it, and that is not very attractive. So the health technology developer has to submit a package for health technology assessment. And this is where the question is asked, does this intervention offer useful, appropriate and affordable benefits for patients? So it's a slightly different question.

Anke
00:03:45
And the evidence that is taken here is on one side as well coming from the clinical trials. But here the assessment is much more comparative that means what is the current standard of care and compared to the current standard of care? What do we get? Right. Right. So health technology assessment bodies usually only do the assessment. They make the recommendations at the end. But they don't make decisions right.

Caitlin
00:04:14
But then there's also if patients do get access in the end I assume there's ongoing reviews to check that it's safe once it's in larger populations, once it's in the real world to check it's continuing to be effective and cost effective.

Anke
00:04:27
So again, there's the regulatory side. The continuous activity there is really more focused on the harms is the collection of side effect the monitoring and taking action. If there is something coming up which is more severe than expected, that may then lead to a blockage of selling that product. Further, the house technology assessment, how that continues is a bit different. Okay. And it depends really on country to country.

Anke
00:04:58
But there is some continuity and ideally they should like every three years go back. Does it deliver the value we were expecting. If not are we still willing to pay for it? Do we have to renegotiate? And so on and so on. And at some point at the end of the lifecycle, when there are new products which have come to the markets, then there may also be an assessment to decide whether to disinvest.

Clarinda
00:05:23
Yeah, do the regulatory authorities and the HTA bodies talk to each other.

Anke
00:05:29
It depends. So the regulatory bodies are usually on the national level or multi country level, like in the European Union. It's done on a central level. The European Medicines Agency. However there are about 50 regulatory organizations, competent authorities which are based in the countries and have different purposes, and they collaborate among each other. For HTA, it's a bit different. HTA is usually on a national level or on a subnational level, like in Italy and in Spain, you have regional bodies with different definitions, or sometimes it's in an organization like maybe in a health provider organization or a health systems organization in the US or in Europe.

Anke
00:06:26
In hospitals, for example, they may have their own HTA unit. And so it's not all HTA people talk all the time to the regulatory people, but on certain levels where their interests overlap, they may collaborate from time to time, but they have separate tasks. Yeah.

Clarinda
00:06:44
Got it.

Caitlin
00:06:45
So thank you for that wide overview. I think what would be great now is if we could zoom into each of those steps a little bit. So firstly, with regards to regulatory affairs, could you give us a bit of an overview of what that process looks like and what criteria would be needed for a product to be successful?

Anke
00:07:08
Perhaps I'd take a step back to this point of medicines development. So we have this health technology developer. I guess we focus here on medicines more than medical devices or diagnostics. And the clinical development happens in phases which most people have heard of phase one, two, three, which is basically an incremental testing of this compound in the target indications. And the way this is structured is that at the end of the development, all data are there which can be submitted to the regulatory authorities.

Anke
00:07:45
So once these data come to the authorities, the development is completed. They cannot change anything more. They have the data they have. So they try often already earlier to interact with the regulatory authorities to get input. Do we collect the right data is destroyed. Clinical trials we are doing. Is this the right endpoints we are using to maximize their success rate. Yeah. So now they have this dossier. And when I mean you see that I'm already a bit gray. So I've been long in the business. When I was younger they would really have trucks of files which would be brought to the regulatory authorities where they had like all the data, all the clinical trials stuff, which they had to go through. Nowadays that's electronic, but it's still a lot of information which is submitted as a big file to the regulatory authority. There's very clear guidance on what data have to be submitted. And then there begins this review process. And I guess the success criteria is good data. And does it do more good than harm for patients? The good for the regulatory authorities is assessed by looking at efficacy, which is in a positive sense, the endpoints which were in the clinical trials and how much of an effect can be seen there.

Anke
00:09:15
And the other side, the harm. That's basically the adverse events or side effects. It's definitely unintended. But when I studied pharmacology in university, my professor always said there is no effect without a side effect. And it's only the question here is how big is the side effect and how acceptable is it. Right now the issue is that at the point when this is assessed originally we only have the data from the clinical trials. So that is patient populations from a few hundred, maybe a few thousand, but it's still a limited size population. Let's say altogether we had 10,000 people in the clinical trials. And there is a side effect which only happens like for one person and 100,000. Then there is a high chance that they never saw this side effect in the clinical trials. So that is the caveat. And therefore the regular authorities basically continue working after giving the market authorisation by asking to monitor these side effects in the use while the product is on the market. Thanks.

Clarinda
00:10:29
That's very helpful. So who then are all the players involved at this stage apart from the regulatory authorities? Is there a constant back and forth with the pharma company or patients involved at this stage?

Anke
00:10:43
I mean, what does stakeholder mean? Stakeholder means anybody who has an interest in this.

Anke
00:10:50
Yeah. So pharma companies have a big interest in it. And the regulatory agency, they can go back to the pharma company and say, we don't understand why did you do this? We don't understand this. So there are points where they can have interaction or they can ask for additional evidence if they don't find what they need. Then in terms of involvement, they will definitely involve clinical people who have gained experience, maybe during the clinical trial or who can give other relevant input into this. And they may involve patient or patient representatives for different reasons during the process of regulatory assessment and the.

Caitlin
00:11:33
Role of the patient. Then just thinking about what you are saying about the sort of risk versus benefit, looking at a product leaflet for any medicine, quite often they have a really long list of scary looking side effects for example, and I think that would put a lot of people off. But a patient who is living with the disease might often have a really different perspective on that, because they see the benefit as really outweighing the potential risk of an adverse event.

Caitlin
00:12:02
So do patients have a role in that decision making about whether the benefit outweighs the risk?

Anke
00:12:09
Yes, it depends on the agency. So you have in the US, you have the FDA, the Food and Drug Administration and Europe, you have the European Medicines Agency, and in China you have the Chinese FDA. So you have all these different regulatory organizations, and they all have different processes. The FDA and also the European Medicines Agency, they have defined processes on patient involvement. They have defined requirements on like how patients should be involved in the clinical trial. Specifically, the FDA really asked for with all the documentation submitting on how patients have been involved or our patients insights have been used in clinical trials to make sure that this is really relevant to the way patients experience their disease. And then in the processes, patients can be involved as being members of oversight committees. Patient can be involved by being asked specific questions about specific technologies. Experiences they may have with those patients can be asked by giving input on reports.

Anke
00:13:28
So the report is published and then patients are consulted. Basically read through this report. Do you see anything which doesn't make sense to you. So there are different levels on how patients can be involved. And thereby they also shape the foundation for the decision.

Caitlin
00:13:46
You mentioned that the EMA and the FDA have processes kind of in place to involve the patient. How recent is this development and how is it evolved over time?

Anke
00:13:58
It's not that recent. EMA, as far as I know, has already, since a long time, involved patients or other stakeholders in in different ways. It's maybe in the last 20 years that it's become more structured and more defined in the guidance and the regulations. Traditionally, patients were not involved. And why has that changed? I think that has changed. On one side, in the 80s, when the HIV crisis came up and suddenly there were patients who were well educated, well spoken out, they insisted on having a right to their health. And that was really quite new at that time, because before there wasn't any channel to make that happen.

Anke
00:14:43
And then in the 90s, the availability of the internet and the availability of so much information through the internet has led to a much higher level of literacy, of demands from the patient side, and therefore a higher ability to participate in these processes. I think things went a bit hand in hand there to allow for, let's say, a democratization of the processes. Yeah.

Clarinda
00:15:11
And I mean, I would think that all of this is quite technical and especially the regulatory approval process. So what would the kind of qualifications or patient need to participate in this sort of process?

Anke
00:15:24
So basically there is no qualification needed. Any patient has the qualification of having experiences with their own health, with their body, with the care they receive, with the relationships to the caregivers they have. And this is already a lot of experience, which would be important in the decision making process basically. So that is one side. However, you can see it like a little bit like a career. So basically you could be somebody who says, this is my life and I want to contribute my experiences to this process.

Anke
00:16:02
But you could also say, actually, I want to be part of shaping the process. And then obviously you need to understand how the process works. You know, you need to understand how decisions are made and how the evidence is evaluated and so on and so on. So the more you want to influence the process itself, the more you should understand how these processes work. And sometimes these authorities, they would love to talk to people who don't have any deformation or so in terms of knowledge. So you don't know too much because they want to know the native experience, basically, right? Right. But for other things, you do need to have some understanding of the system. Right?

Clarinda
00:16:51
So what I'm taking away is that for many patients, it might seem like a black box. This whole regulatory affairs process and the idea that it only takes really highly qualified individuals in a very technical field to participate. But it's heartening to know that all they need to do is bring their lived experience. And, you know, in some cases they can participate like that.

Clarinda
00:17:15
But if they want to do more, there is also room for them to learn and upskill and then potentially contribute at that level.

Anke
00:17:23
Yes. I mean, we also have to remember that not all patients want to contribute to this, but for the ones who would like to contribute or who are asked to contribute, I think there is no reason to have fears and not to do it. Because basically what you need is the experience as patients. That's what the actual expertise is.

Clarinda
00:17:46
So then for patients who do want to get involved. How would they find out about these opportunities and how might they begin to get involved in regulatory affairs?

Anke
00:17:56
Okay. There's a few things there. The most important is you need to understand how the system works where you live. So that would be the first step is try to figure out what is the regulatory authority which is relevant to you, and then look on their website if they involve and how they involve patients, how that works, how you can alert them about your willingness to participate, and so on.

Anke
00:18:24
The other thing for participating in the regulatory processes is that they really want to have patient input that comes from the patient. They don't want patient input that comes from others. So what they don't want is patients who are instructed by industry what to say when they come to authority. And I think that is right. And we all wanted this way because we want to make rational decisions on these things. And we want to have independent decisions and a high level of transparency in that. And therefore if you collaborate with industry that is great, but it may prevent you from collaborating with the regulatory or other authorities at the same time, if it's a patient organization, then for them, it is also very important to know about this potential conflict of interests to balance in their activities and to ensure that they keep their independence in a way that it's still allows them to do the things they want to do.

Caitlin
00:19:35
Yeah, I think that's a really interesting point. Just because as a patient advocate, I suppose you almost want to get involved as much as you can.

Caitlin
00:19:44
But there are rightfully so a few of these conflicts whereby you can't be seen to be biased towards a particular company. If you're then reviewing, you know, the regulatory process that they're going through from the other side. So I think it's a really good thing to inform more people about. And from a patient organisation perspective, of course, it's amazing if the patient organisation can work with the pharmaceutical industry or company to support with their trials and make sure that they're fit for purpose, but then you have to make sure it doesn't look too biased when you come to the regulatory stage of it. So it is quite a complex and maybe nuanced problem, I think, in the patient advocacy community.

Anke
00:20:30
I agree it is, but I think it's also a matter of setting priorities for yourself. If you find an opportunity as a patient organization or a patient to engage with the company in a real sense, to partner, to co-create a product, which just makes sense for patients, then I think this is a huge opportunity to do so.

Anke
00:20:53
You will probably not be asked to come to the regulatory authority on the same product, but you have a huge opportunity to shape the development. But in other instances, if it's only about being invited to webinars and seminars and nice dinners or something, maybe you set your priorities somewhere. Yeah.

Caitlin
00:21:16
That's really helpful advice. And I suppose it's nice in a way, because even if you can't support by reviewing the regulatory dossier that they have submitted from the regulatory side, hopefully that dossier will be stronger if you've been involved earlier. So having patience and maybe even having different patients along the pathway to make sure that what's actually being done at each stage is robust is a good way to make sure that only the best products are getting approved and give it to patients. Yeah.

Anke
00:21:47
One thing I would like to say is, as a patient, usually you are not reviewing the dossier. And I mean I'm not reviewing the dossier. That's a scary thing to do. Quite happy to leave that to the people who know how to do it.

Anke
00:22:01
Yeah. You are more shaping the questions they are asking. You are more shaping the interpretation. What does this evidence mean to us? Or so yeah.

Caitlin
00:22:10
That's less scary. Thank you.

Clarinda
00:22:13
So I think that we've laid it out that overall regulators are welcoming of patients and keen on having patients on board. What would you say are some of the barriers to patients actually getting involved? So one you mentioned for example, is if there's a conflict of interest and a patient advocate is already working with an industry partner for example.

Anke
00:22:35
A barrier could also be that the definitions of conflict of interest are so narrow that they prevent a lot of patients for different reasons, to participate. Each of these organizations, they define what conflict of interest means to them. So usually, I mean, what should be standard in these processes is a declaration of interest so that everybody who participates the researchers, the patients, the clinicians, that each of them has to declare the interest. I'm a member of a patient organization, this one I'm paid by this company and so on.

Anke
00:23:12
And then it's up to either some committee or a standard process to define where is the level where we say this person has a conflict of interests when they work with us. You ask about barriers. I think the complexity of the processes is definitely a barrier for many people because they think like what? Yeah. Read the documents. No. Forget it. The other barriers. Once they are in these committees, sometimes it's the existing or perceived hierarchies. Like, let's say there's a clinician sitting at the table. There's somebody from the regulatory agency, some industry person and the patient there is even if it's not defined in the room, there is a certain hierarchy which often puts patients off a little bit, then a high barrier or wrong expectations. So what did I actually expect to achieve when I went into the process? And it's very clear that patients will not make the decision. They can give their input. And if I go into this as a patient and I say like I really want this technology and then I'm disappointed if the technology doesn't come.

Anke
00:24:34
That's not why I was involved it. I was involved to help them to understand better what my needs are, what my expectations are, how much the technology perhaps meets that, and so on. And then what? Probably the biggest barrier is not even knowing about the opportunity and knowing about the opportunity, not knowing how to realize that.

Caitlin
00:24:58
And precisely why we wanted to talk to you today and release an episode on it, because we both work, you know, professionally in the medicines development space in some aspects. And a surprising number of people I know aren't really fully aware of what these processes are. And I think, like we've said before, it's quite daunting for patients who maybe don't really know what the processes are and how to get involved. So it's been really helpful having you talk about that. And I just wondered following those barriers that you spoke about, are there initiatives that are being carried out to sort of help remove those barriers. I think just things like education, like the participation training program, they obviously have a lot of resources to describe what regulatory affairs is and how to get involved.

Caitlin
00:25:45
And hopefully, you know, there are some regulatory authorities as well who are trying to make it more accessible to patients. But I wondered if you knew of any other initiatives that were looking to help patients get more involved?

Anke
00:25:59
Yeah, I think you will find these organizations. And you did mention new party already. Often it's also the authorities themselves, if they have to find for themselves that they want to involve patients at certain steps in their processes or all the way through, they start realizing that it's not that easy. And then often they produce materials for patients for the information. And it's like, this is how we work. This is how you can become involved. This is the person you should call and so on. So I think using those resources which are usually posted on the website, that's a helpful step. They also have over the time improve their processes for how they involve patients. So it's kind of learning exercise in a way we started doing it. We saw it didn't work so well. Okay, let's try something else.

Anke
00:26:54
What were the experiences. Are this what it was now let's do it better next time. So I think it's kind of like developing together a lot of information you find also with patient organizations who have done this already. So that sometimes can be a good source to understand what is needed, what was useful, what was not so useful, and so on. Great.

Caitlin
00:27:19
Thank you.

Clarinda
00:27:20
My only last question was what percentage of medicines actually clear the regulatory affairs process and the success rate?

Anke
00:27:29
That's a good question. I think there is an up and down. When you think 20, 30 years back, the refusal rate was about 50%, both for the FDA and the EMA. But we've all learned and now it's around 10 to 20%. Sorry.

Caitlin
00:27:48
And that's ten for 20%. Fail, fail. Oh okay. So actually the majority make it.

Anke
00:27:55
So it's basically it means companies or technologies are much better prepared when they come to the process today. And maybe it's also a bit more transparent today, right. That the chances of getting the market authorization are better.

Clarinda
00:28:12
Yeah, that's a great overarching context to have because we are aware of the spends and the kind of timelines the drug development takes, and then you would hope that more and more drugs are clearing that process because of good evidence.

Anke
00:28:28
So I mean, there is a few buts there. One is there is always a research question. And in the regulatory affairs it is focused on the indications that were asked. Basically you had clinical trials that asked certain questions. So you cannot get more market authorization than was proven in your clinical trial basically. Right. So you have these labels which are usually quite narrow. And then you can only use this in this narrow indication and you get a broader indication you need to submit more evidence. Then maybe at a later stage you get a broader indication. So that is one of the limitations of this.

Caitlin
00:29:13
So just to give an example of that, if the trials were only in people aged 16 and over, then the authorisation they get would only be in people 16 and over. But later on if they do more trials in children, they could expand that.

Anke
00:29:28
That would be one example. Yeah. And then the other big thing is the safety aspect. Regulatory authorities are extremely sensitive to safety problems. And that is good. But sometimes it does kill drugs okay. And that's basically also where patients could make a difference where patients can say I have such a miserable life. If I get this bit of improvement in my quality of life, I'm quite happy to accept this side effect. Yeah.

Caitlin
00:29:59
Okay. Thank you, Anke. That's really helpful. I certainly understand a bit more about regulatory affairs now. So just moving on then to the next step in the process. So once a drug has been approved as being, you know, safe and effective by the regulatory authorities, it moves into a HTA process. Now my first question that I just want to clarify because I think it confuses people. So HTA stands for Health Technology assessment. So what is a health technology?

Anke
00:30:30
A health technology is any intervention which is used to improve the life of a patient. It could be a medicine, it could be a medical device, could be a diagnostic, it could be a vaccine.

Anke
00:30:44
It could be an education program or procedure, like a combination of different interventions. So it's a very broad expression.

Caitlin
00:30:54
Perfect I think the word technology sometimes confuses people. Yeah. But so that's that the way could you tell us a little bit more about what the HTA process is.

Anke
00:31:05
Yeah. So let's perhaps first ask why HTA we do have limited resources. Right. The country we live in has a general budget. And of that general budget, there are 10 or 12 or 13% spent for health care. And now there's so many new technologies coming in. What do we do? So we have to have some process which helps us to within the limited resources, we have to make good decisions on which technologies to adopt and which ones not to adopt. I mean, we only want technologies that improve health and do not bankrupt our system. Yeah. So what is health technology assessment? It's an explicit process. It's multidisciplinary and considers all the evidence that is there to understand the intended and unintended implications of the technology and the consequences in terms of health and in terms of cost.

Anke
00:32:12
Yeah.

Clarinda
00:32:13
Since you mentioned all countries budget, and I think that you were referring, by and large to the European framework, where it is the government that funds health. Essentially. What about a system like the US where it is insurer based? What are the differences between those two?

Anke
00:32:32
In that case, well, the biggest difference is that there is only a limited use of HTA in the US, although this is really changing. But basically, if you look like how does health care works? You have two main models. One is the Beveridge model, which is the example is the UK where you have a text based system and all the health care is paid out of tax. And so you have basically a national health care system. And the other system is the Bismarck model, which is the originally German model, where there is something like a solidarity principle in a social insurance. So everybody pays into this insurance and then who gets their services or the health care coverage. Those are the main systems. Now then you have totally private insurance based systems, often in low income countries in the US is basically a mix of all of that.

Anke
00:33:32
Now, health technology assessment would be valid in both the Bismarck model and the Beveridge model. It could be done on a national level. It could be done on a regional level or on a population, or like certain organizational level, where it's usually not done is for people who pay out of pocket or from like totally private insurance. So, so often, for example, in South Africa, you have a lot of private insurance based healthcare, and you have a little bit of public. And the initiatives now to introduce to they really try to get the private insurances on board. So they may have a mix.

Clarinda
00:34:13
So in a country like South Africa, like you mentioned, where it is private insurance based, I assume that the end stage in the process is the regulatory approval. And once that's done, then it's completely up to insurers whether they're ready to pay or not. And then I question what would be the purpose of introducing HTA in that system.

Anke
00:34:34
I mean, the question is why do we have healthcare systems anyway? Why don't we leave it up to the people to care for their health? Am I interested in the health of my neighbour? Not really.

Anke
00:34:44
So yeah, before Bismarck introduced the first health insurance, that's basically what we had. And what many people in low and middle income countries still have. Yeah, you are responsible for your health. And if that doesn't work, maybe your family cares for you. And then that often means because of high costs and everything that they have to sell their house, they lose their jobs. They don't earn money anymore. There is financial crisis and that's not good for the society. And the trick of health care systems is really we keep people in the system economically independent, basically by caring for the sick people. Ideally, we even cure the sick people so they can go back to work and again contribute to the economic success of the society. So when we come from that perspective, it would be good to make health care decisions that are fair and equal for everybody in the society, that they have equal access to high quality health care, but only in a way that it's necessary and useful.

Clarinda
00:35:53
Yeah. So the World Health Organization has a goal of universal health coverage.

Clarinda
00:35:59
And I assume then that in that framework is where health technology assessment would play a significant role in bringing universal health coverage to all countries.

Anke
00:36:12
That's definitely a goal, is to increase the use of health technology assessment to make decisions more transparent, more evidence based, and more with the overall objective of equity and fairness.

Clarinda
00:36:27
Thank you. That was very enlightening.

Caitlin
00:36:29
So I was wondering then if you could talk us through what people look at during a health technology assessment. So it's been approved at a regulatory level to say that it's effective and it's safe. So what is it that the health technology assessments are looking at, and what factors influence whether a drug is successful or not in this process?

Anke
00:36:50
So as I said, it's the intended and unintended consequences of the technology in terms of health outcomes and in terms of financial consequences. And what is the evidence that is used. So let's say the product has received market authorization, but it's not marketed yet. Then the only evidence we have is from the clinical trials. and maybe, depending on where we are.

Anke
00:37:21
Some real world evidence from other countries and most often the clinical trials. Maybe they are comparative, but maybe the comparator that was used in the clinical trial isn't exactly what in real life is used in our country, right? So how do we make a fair comparison between what we currently have and what the data we have on the new technology to do? So often we use modeling techniques. That means we simulate the reality in a mathematical model, which helps us to compare against other therapies which may be used currently by introducing those into the model. And then we base these models on the numbers we have, but otherwise we use the same evidence which comes from the clinical trials. We just may look with different eyes on the evidence. It's much more health benefits in comparison to current care and health benefits could be in terms of length of life, quality of life, different specific aspects of quality of life. It could be other things, but usually it's something which is relevant to the patients in and then in combination with a price that is asked from the company, it's fairly easy to calculate if ten patients take the product, which costs $10,000 a year, then that is $100,000 for the health care system in terms of those costs.

Anke
00:38:57
Then they have to drive to the hospital. So it's it's not the price of the product, it's the total cost of treatment, including the treatment of the side effect, for example. And then on the other side we can say, what does it mean in terms of savings? Like for example, maybe the patients are faster out of the hospital. That hospital is safe. That right is clear saving. So we can calculate all that. So we differentiate between direct costs and indirect costs. And then indirect medical costs or indirect non-medical costs. Non-medical costs would be something if I go to the hospital I have a little child, it needs child care and so on. That's not really a medical cost, but still I have to spend for this, right? And it depends on the guidance of the Health Technology Assessment Agency on what they accept as a cost. Okay. And these guidances are published. And then if the company wants to bring to the product, they have to produce either these models and submit them in the specific context.

Caitlin
00:40:07
So that's quite a big task.

Anke
00:40:09
Yeah. And sometimes just to make it even more complicated, it's also what are the outcomes we are interested in? For example, the UK puts a lot of emphasis on cost per quality, and quality is it's a strange measure. The full name is quality adjusted life here. Germany. They don't really like that measure okay. They like effect. So cost effectiveness is really only one part of the story. And it's used in some countries as a very important part of the story, which kind of guides the whole process of health technology assessment. But there are other countries, Germany, France, Japan, who put the first emphasis on additional benefit if they come to the conclusion that the product doesn't deliver additional benefit, they don't even look at the cost. Okay, okay. It's only in the next step that they were say, okay, how much do we have to pay for this benefit? Interesting. Yeah.

Clarinda
00:41:09
So I wanted to ask then my understanding is that while we thought that regulatory affairs requires so much of evidence and it does, it does seem like the process actually requires even more evidence and more varied evidence sources and things like that.

Clarinda
00:41:28
So what is the timeline then, from, say, a drug getting marketing authorization to it, actually even reaching the technology assessment.

Anke
00:41:38
So we have health technology assessment since many years. The UK introduced this sometime in the end of the 90s, I think. So manufacturers tells technology developers they know about this. They know it already when they develop their products. So they do it in parallel. Basically, they generate evidence which helps health technology assessment agencies to assess their part. So that is often not the big delay in the process. The delay may be because of structural reasons, political reasons and so on. So there are few countries who allow aftermarket authorization. The manufacturer can market the product, and it has to be reimbursed unless a health technology assessment comes to the conclusion that it's not worth the money. Oh okay. Okay. For example Germany. So there is a high pressure on the health technology assessment unit to as fast as possible do the health technology assessment because other one is the system has to buy this product for a high price.

Anke
00:42:41
Yeah. Then there are other countries who have these precious in the health care system. In the financial system, they are not so keen on getting these expensive new products. Also, there is a risk in using new products and the risk is they have only been tested in the clinical trials. So sometimes there is reason to say let's be a bit slower with that lets the Germans take it first and then we'll see how that works. So you see the different mechanisms which play and different interests again on how this shapes out. So this can take a half a year or a year or three years. And it really depends on the environment, on the system, on how the structure is and how the process is and where HTA falls into it.

Caitlin
00:43:32
Interesting. Thank you. It does seem to be quite complicated and differs across the world, but I think it's been really helpful for you to explain how it varies and overall how it works. So what would a patient's role in to be?

Anke
00:43:48
It's a bit similar to the regulatory process.

Anke
00:43:52
I mean, basically what the expertise of the patients is, is the experience with their own disease is the experience maybe with their peers, they know the community of patients. The difference between patients and they know their interactions with the healthcare systems. And that is the knowledge they can bring into the process, obviously in the HTA. This is essential knowledge because here it's about how useful is this technology in our context in my country and here, it's really where the patience they can bring in a lot of information on this context, plus their own experiences, plus their own expectations, feasibility on using the product. If I have to go to the hospital to get infusions, that may work quite well. If I live in a city and I kind of take the public transport, it may not work so well. If I live somewhere in the countryside where I need to take a car for three hours to go someplace, and I don't even have a driver or so. In principle. People know about this, but the patients know extremely well about this.

Anke
00:44:59
Yeah. Now how can they contribute? Again, it's different from country to country, but there are different levels. So sometimes patients can contribute actually and shaping the whole process. They can be in some committee or advisory board where they can help to advise the agency in how to shape these processes overall, or with each specific to on what makes sense in terms of patient involvement and not, for example, in Wales, the Health Technology Assessment Agency, which is mostly focused on procedures and devices. They have this committee which for each technologies goes through a checklist, basically to say what type of patient involvement makes sense with this technology assessment. So that would be like on a bigger level helping to make this useful and relevant. So the first thing for health technology assessment agencies is to know about these new technologies coming up so they can plan. What they do is something called horizon scanning. So they look up what is coming and how patients can participate in that. Theoretically they could. That is not extremely established and not all agencies do this horizon scanning.

Anke
00:46:18
Then once the technology comes to the assessment, then the agency has to think about what is actually the questions we want to ask about this technology, what is important to know. And that is called the scoping. So they kind of produce a framework and how they assess this technology. And in this framework they will ask about like what is the population for which this technology will be used. What is the intervention. So that's more the technical description of the new technology. What is the comparator, what is the actual treatment they are getting and to which we would have to compare? And then what is the outcomes we are interested in. And all of these aspects patients could actually contribute to. That's the scoping. Then at some point there would be a call to patients to give input. Patients need to be aware about this opportunity. And that's where patient organizations can help to spread that knowledge because not every patient goes to the website yet. Then there is evidence collection. Patient organizations could collect evidence, for example, do surveys with their members to respond to specific questions the agencies would have.

Anke
00:47:37
Sometimes they ask for patients to interview. Sometimes they ask for patients to participate in focus groups. Then there is, once they have collected all the evidence, the assessment of the evidence, and they produce a report. The report is published on the website. And then patients often are asked for consultation to read through the report and give their input. So that's the consultation. And then patients can be in the appraisal committee in some countries where they actually sit and discuss this evidence. What does it mean and how do we want to interpret it? In our country and in some countries, they can vote in the end of this appraisal. In other countries they cannot. So then there is a final report coming out of the HTA, which has some recommendations. And this goes to the decision making institution committee or whatever it is. Who will then based on the recommendations from this report, they will make a decision. Usually the decision is separate from the health technology assessment. So yeah.

Clarinda
00:48:43
So I think that one point that you made when you were talking about regulatory affairs also applies here, which is that, you know, if a patient is involved in a regulatory affairs or a health technology assessment committee and then gets upset that the product is not getting approved or the decision is not working in their favour.

Clarinda
00:49:04
Do you think that there's an inherent conflict of interest that they bring in terms of how they are able to be objective in that situation? I guess because they really want this product to improve their quality of life. So I'd love to hear from both of you about that.

Anke
00:49:19
I think if you want to make a valuable contribution to health technology assessment, somehow you have to change your attitude from being an advocate to being a partner in this. Because in the end, what we should want is the best decision for the patients in our countries or the population in our country, based on all the best evidence we have. And you said we really wish that the medicine improves our life. Yes, I absolutely agree, but that doesn't make the medicine a good medicine. Our wishes and hopes. It doesn't mean that the medicine is valuable in our context, and that we need to understand the assessment is done to make a rational decision about, does it give added value in our context, and is it worth the price to pay for it? Because if we pay too much for it, there will be other patients with other diseases who don't get access to their medication or whatever because there's no money left for them.

Anke
00:50:22
What helps, probably, is really to also educate people who want to be involved, that their involvement means that they need to contribute to making a fair and legitimate decision. And that sometimes doesn't mean that the technology is approved, but they had the opportunity to give the best input they could give.

Caitlin
00:50:47
I totally agree with everything you said, Ankur, but I think sometimes, especially if you're in a rare disease where there isn't currently a treatment, the benefit can be huge, but the price is also huge. And I think what's really difficult actually, from a patient perspective is how do you put a price on someone's life? And I think thinking of it in the wider perspective, like you said, is helpful to say, is it worth millions of pounds to help a few people versus taking that away from maybe thousands of people that you could help with the same amount of money? So thinking of in that wider context is helpful. But when you're honing in on a specific technology that could help you or your family member specifically, I think that's really difficult.

Caitlin
00:51:29
Not to be biased, but all you can do in that sense, again, you're not making the decision, so you're not really being biased. You're just providing your true experience and feelings, and I suppose hope that that is enough evidence to prove it is worth the price. And I was in quite an interesting situation, actually. So my experience with this is that a drug had been approved, and I'd actually had access to it for three years. And the HTA agency in the UK, which is called nice, had given a three year deal so that everyone had access to that drug for three years, and then they were going to reassess. So the situation I had was that they reassessed it and actually said, oh, based on the evidence of the last three years, we don't think that the price that the company has given us is effective. So that was a really interesting position because I'd actually firsthand not only experienced what it's like without the drug, but then I'd had three years of experience with the drug.

Caitlin
00:52:26
So if cystic fibrosis and the CF trust in the UK had a submission, and then also they'd called for people to submit their own experiences, but what was really interesting was just having a read of what the nice sort of review said. It was only a draft guidance, but they said it wasn't cost effective, and when I read through and looked at their models, I realised they didn't necessarily maybe understand the wider context. So they have the numbers and they have those economic models. We were talking about a direct and indirect costs, but what does that actually mean in terms of quality of life and contributions to society. And I think a lot of people wrote in to say these numbers are one thing, but have you considered the fact that I've got a full time job and I'm doing a podcast and contributing to society and paying rent, but had I not had that drug, there's a good chance that I would be sitting in a hospital right now taking up a hospital bed, waiting for a lung transplant, and then after that, my quality of life might have improved again.

Caitlin
00:53:25
But that costs an awful lot of money to get that transplant and the drugs that are involved and the tests that are involved. And from a day to day, the fact that I don't cough anymore, I can go outside, I can spend time with my friends without coughing and spluttering, without being shouted out on the street, because they think that I have covered all sorts of these small angles that aren't captured in just the data. And I mean, I'd like to hope that that's something as well, that really provides some colour and real life experience and light to what those numbers actually mean and to what those numbers don't capture. And I don't know if it was the patient voices that contributed or whether it was further evidence that was submitted. But nice did change their mind in that situation.

Clarinda
00:54:07
So yeah.

Clarinda
00:54:09
That's excellent.

Anke
00:54:10
I think that's the kind of things which really make a difference.

Clarinda
00:54:14
So Anke, this has been excellent. We've really learned so much and it's been just so rich and so insightful. I feel a little more confident about being able to explain these processes to other people if I have to, and I have you to thank for that.

Clarinda
00:54:29
So just before we wrap up, we would love to know if you have advice for patients who would like to get more involved in some of these processes.

Anke
00:54:39
Yeah, I guess the biggest advice is understand your system, understand what are the opportunities to be involved. I mean, test the waters, perhaps try a bit more carefully first. But if you want to become more involved, then do one of these trainings. You both have the experience with the potty training. There are patient organizations who offer these kind of trainings. There are sometimes there are universities who offer these trainings specifically for HTA. There's a new program developed by New Party for European Patients to be involved in the European HTA process. And there is another European training from the program called Yucaipa EU Coppa, which is also for patients, super good content of these trainings and so on.

Caitlin
00:55:32
Thank you. And I certainly agree that although it seems daunting even just in this conversation, it's made me feel a lot more confident in what those processes are.

Anke
00:55:42
One more thing to keep in mind when you start this endeavor is this is daunting for you, but it's also daunting for the people on the other side of the table.

Anke
00:55:54
The researchers. They need to learn how to interact with patients. Often they are good researchers, and this is what they have learned to deal with evidence. But to deal with stories or qualitative evidence is a bit more difficult for them. And so I think we all need to be aware that this is a learning process where both sides learn in the communication with each other, what it means to involve patients or to be involved.

Clarinda
00:56:23
Right. Great.

Clarinda
00:56:24
Yeah. And similarly, just to close this off, what would be your advice then for some of the other stakeholders, the regulatory officials and the HTA bodies who want to involve patients for.

Anke
00:56:36
Well, we have recently concluded our European project on stakeholder experiences with patient involvement in European HTA processes, and we've published a report on that, which is kind of recommendations along the HTA process on how to do things in a way that they are perceived well by the stakeholders who participate in it. And we are worked with patients. We work with HTA people and industry people on this, and there are few things which come to my mind.

Anke
00:57:09
One aspect I really, really like is the organizational involvement. Start to involve patients when you build the processes to get input on the high level part, and obviously training and information is like give information that is relevant for patients. That could, for example, include our summaries in patient language, which you could ask the industry to submit together with the rest of the Dosti patients don't have to become experts in health economics and whatnot. That's not the reason they are involved. Yeah, but they should understand why the questions are asked, how they can best respond, what is the part the agency is interested in, and how can patients bring this part? And patients should get feedback on what happened with your input. How did we consider it in the report? How did we consider it in the appraisal maybe, or in the decision? And if you don't give this feedback, patients do this once, maybe twice. And then they say, like, I have no clue what these guys are doing, but I spend my time with better things.

Clarinda
00:58:21
Thank you. That's great.

Caitlin
00:58:23
Thank you so much for everything you've said today and for your time. I think it's really helped to unravel what is a really complicated and I think a topic that people aren't very aware of. So I'm sure this will be extremely helpful to a lot of people who have heard of regulatory affairs and HTA, but don't really understand what that means. So thank you so much for joining us today.

Anke
00:58:46
Yeah, happy to join you. I hope I don't confuse people more than they were.

Clarinda
00:58:51
No, no.

Anke
00:58:52
Not at all.

Clarinda
00:58:52
It was very well simplified.

Clarinda
00:58:56
Thank you so much.

Clarinda
00:58:58
So Caitlin, I think that was a really informative discussion. I learned so much. I was wondering if you wanted to talk about some of the top things that you learned.

Caitlin
00:59:08
Absolutely. So I think I learned a lot about how these processes work. They're obviously quite complex, but I now understand the objective behind them a lot more. And I think what really stood out for me is the value that patients can bring to these processes from a regulatory first process.

Caitlin
00:59:25
Obviously, the idea is to assess benefits versus risk, and I think it's difficult to do that without the patient perspective, because the benefits and the risk will probably be different from a patient perspective than from an outside perspective. Likewise, with the HTA, patients can provide the color to all of the data and all the cost models that they use, and really show a more holistic view of how that impacts the patient of the healthcare system and society.

Clarinda
00:59:57
Right. And one thing that I learned that I was not aware of was that perhaps if patients are closely collaborating with pharma in the drug development process itself, then they might not be able to get involved in regulatory affairs and to because that might be a conflict of interest. But it is fine, really, because it means that patients are contributing somewhere in the timeline. It's fine to contribute whatever seems best suited to you.

Caitlin
01:00:25
Yeah, absolutely. And what's really encouraging as well is that I know many people may feel a bit worried or scared or have imposter syndrome about being involved in regulatory affairs or HTA, because the processes aren't as well known.

Caitlin
01:00:41
But what's comforting to hear is that firstly, they are really encouraging patient engagement and even in some cases specifically looking for people who just live with the disease and don't necessarily know a lot about the processes, but also the main expertise they're looking for is that lived experience. So by definition, any patient can get involved. So you shouldn't feel like you can't contribute meaningfully.

Clarinda
01:01:06
I agree, and I hope that more patients do take the opportunity to get involved in some of these processes.

Caitlin
01:01:14
Thanks so much for listening. This has been not just patience with our guest doctor Anke-Peggy Holtorf and your hosts Caitlin Rich and Clarinda Cerejo.