Infarmed: “There are companies that have very high quality standards and others that have very… debatable quality standards”

Cannareporter spoke with Vasco Bettencourt, Director of the Licensing Unit and Coordinator of the Cannabis Office for Medicinal Purposes at Infarmed — National Authority for Medicines and Health Products IP, and with Ana Paula Martins, from the same Medicines Evaluation Department Office, to better understand how the medicinal cannabis industry works in Portugal. How are companies licensed? Why are there no more authorizations for placing on the market (ACM)? When will medicinal cannabis be reimbursed in Portugal?

[Disclaimer: Please note that this text was originally written in Portuguese and is translated into English and other languages ​​using an automatic translator. Some words may differ from the original and there may be some typos or errors in other languages.]

Companies operating in the area of ​​medicinal cannabis in Portugal continue to increase and neither do licensing requests to Infarmed. This year alone, Infarmed has already issued 76 new authorizations for the cultivation, production, import, export and distribution of medicinal cannabis. In addition to these, there are another 265 requests in the post-decision phase. But with all this business activity, and five years after the legalization of medicinal use in Portugal, patients can only legally access a single product in pharmacies, with a proportion of cannabinoids that are difficult to apply: 18% THC and 0% CBD .

In this long interview, we address all these questions. We also asked Infarmed about the possibility of simplifying processes, to facilitate patients' access to the plant, among other issues that plague the cannabis industry and Portuguese patients. Read it here in full.

In Portugal, cannabis has been legalized for medicinal purposes since 2018. There is regulation, but so far we only have one flower available (from Tilray, with 18% THC and less than 1% CBD) that doctors can prescribe and that patients can use legally. There are no oils, there are no other preparations, there is nothing else other than this flower. Why?
Ana Paula Martins (APM): There is only one flower because companies had to start the production process here in Portugal and, in addition to the investment being heavy and time-consuming, it also involves a series of tests and procedures that they have to carry out on their plants or their preparations or extracts. , and all of this takes time. Companies have to do what is called in pharmaceutical jargon and regulate the “validation of manufacturing processes”. They have to demonstrate that when they use a certain piece of equipment they always put the plant in the same conditions and the plant goes in and out in the same way every time they put it there. And it's not always easy, because they have to have “pilot lots”, then they have to transfer to “industrial lots” and, therefore, all of this takes time. Imagine that you have a line that makes the cut or the trimming of the flowers and, when they leave there, they have to demonstrate that the flowers have not been altered, that the content of the various cannabinoids has not changed in this process, and then in the drying process… All of this ends up not being easy for companies. This is in relation to the flower, which would be the simplest to put on the market. Regarding extracts, in addition to these problems of “validation of manufacturing processes”, they also have “validation of the extraction process”, that is: under what conditions, at what temperature, how long, all these types of things that companies have to demonstrate. Basically, what they have to prove is that, using their manufacturing process, they can always produce homogeneous batches.

Is there any variation margin for these products?
MPA: There is a margin. For example, if it is the THC content, it should not vary more than 10% [from the reference value]. In other words: a plant that they say has 20% THC should have neither less than 18% nor more than 22%. Even extending this range to 20% is also not always very easy. And we're just talking about one cannabinoid... When, for example, it's THC and CBD content, things get complicated, because both have to be at the levels they say they are.

Ana Paula Martins, from the Medicines Evaluation Department of the Cannabis for Medicinal Purposes Office, Infarmed. Photo: Renato Velasco | PTMC – Portugal Medical Cannabis

And for this, companies have to submit how many lots?
MPA: The dossier is normally demonstrated in three batches. There may be two pilots and an industrialist, but even so, sometimes things don't go well and you have to do it again. So it's not an easy thing. Anyway, in a herbal medicine, be it cannabis or any other, it is not easy to submit, because it does not have just one substance. A chemical medicine, so to speak, is much simpler, because it has a substance that is 99% pure and some excipients, and that's it.

It's much more stable...
MPA: Yes, and much easier. But in the case of oils, it is even more complicated, because in the area of ​​herbal medicines what is considered the active ingredient is the extract, which is normally the “constituent unit”. And companies have to demonstrate that the extract they produce always has the same characteristics. Regarding the ACM (Authorization to Place on the Market) requests for oils that we have received so far, almost all of them want to use different varieties of the plant to make the extracts, which makes it much more complicated to demonstrate that the extract they produce is homogeneous. Because imagine: today they use a variety that has 10% THC and tomorrow they use a variety that has 15% or 20%. And they have to demonstrate to us that the extract has the same levels of the same constituents, which starting from different plants is quite difficult. We are in this process regarding several ACM requests, in which companies want to use different varieties, which greatly complicates demonstrating the homogeneity of the extracts submitted.

Why submit extracts from different varieties, instead of always using the same one? cultivar?
MPA: You'll have to ask companies about that. From my point of view, it was much easier to always use the same variety. But companies probably want to have some freedom to choose suppliers and if one day there is no one variety they can have another. But, in fact, it makes things more complicated when checking and guaranteeing the homogeneity of the batches produced.

And this is the reason for the delay in approving new products?
MPA: Yes, yes, because if we were to reject it we could have already rejected it. But they fail to demonstrate quality. We [Infarmed] are trying all possible ways, waiting more, trying to provide help, to see if companies can really demonstrate the homogeneity of the batches, because we think it is important that patients, in fact, have flowers and oils of various levels to be used in various pathologies.

“What I find strange is that, so far, we have only received requests for ACM for flowers with a high THC content: 18%, 20%, 22%, but no plants with only CBD or with lower THC” — Ana Paula Martins

So the reason you approved Tilray's flower, which has such a high THC content and almost no CBD, is because the company was able to prove this homogeneity?
MPA: Yes, it's easier to prove because it's just one plant, it's always the same variety and we don't have any problems with using different varieties. What I find strange is that, so far, we have only received requests for ACM for flowers with a high THC content: 18%, 20%, 22%, but no plants with only CBD or with lower THC. I don't know if [the varieties with more CBD] are more difficult to grow, or because companies export a large part of the flowers they grow to Germany and they only want flowers with a high THC content... I don't know if that's why, but the What is a fact so far is that we have not had requests [from ACM] for flowers with higher levels of CBD and lower levels of THC or, at least, more balanced ones.

Vasco Bettencourt, Director of the Licensing Unit and Coordinator of the Cannabis for Medicinal Purposes Office at Infarmed. Photo: Renato Velasco | PTMC – Portugal Medical Cannabis

To make this clear, can you say what are considered substances and what are preparations?
MPA: Substances, in the case of cannabis, are basically the dried flower, which can be for tea, for vaporizing, in short, for various uses. Preparations are any extract made from the flowers. Said simply.
Vasco Bettencourt (VB): Anyway, the Decree-Law 8/2019 [of January 15] which came to regulate this, has this definition in article 2. But translating, deep down, that's it.
MPA: Although, finally, preparations can also be, according to the statute of herbal medicines, if the flower is very ground, for example, it can already be considered a preparation.

And the resin, the hashish?
MPA: Hashish is a preparation, clearly, because they extract and process the flower.

At the moment, you have three ACM applications for substances and 12 for preparations.They're all still under evaluation, right? None were rejected?
MPA: Not those. It was rejected at first... And we're seeing if we can reach a successful outcome for everyone. There are companies that have requests for elements, but precisely because of the extracts from the preparations that they are trying to reformulate and carry out other types of analyses, because they also have to better demonstrate the levels of the different cannabinoids they have when presenting the different varieties.

And what is the forecast of whether they will be approved or rejected?
MPA: It really depends on how long it will take. Some companies had to look for other laboratories to analyze these oils, to provide values ​​for more cannabinoids and not just THC and CBD, so it depends a lot. We can't say it will be next month, or that it will be in two months, although we would like to.

So at this point it's not dependent on you, it's dependent on companies presenting new batches for analysis?
MPA: These are not new batches, but rather new forms of analysis and new ways of ensuring that, using plants of different varieties, homogeneous extracts are achieved.

Which companies submitted these requests? Are they Portuguese or foreign?
VB: We can say whether they are Portuguese or foreign, but with the names of the companies there is some reservation here because these are ongoing processes. Of the finished processes we can transmit, obviously. From the information we have is that they are foreigners, most of them, but they have activities in Portugal – I see at least three that are foreigners, although they have operations in Portugal, but the management is carried out by foreign companies and they have mostly foreign investors. . Most of them are international companies that have experience in other markets.

“In a herbal medicine, be it cannabis or any other, [the quality dossier] is not easy to submit because it doesn’t have just one substance. A chemical medicine, so to speak, is much simpler” — Ana Paula Martins

And do you have products approved in other markets?
VB: Yes, at least one of them does; but it does not mean that these are the ones [who are in ACM order table], attention. Germany has a different regime to ours... I'm talking a little by heart, but in the case of Germany, imports for medicinal preparations, that is, what is required by German distributing companies, which in turn distribute in community pharmacies, it is above all the substance, that is, the dried flower. It is then divided into portions at the pharmacy following a medical prescription which must contain the quantities and contents.

In Portugal this still cannot be done, not even in those pharmacies that sell compounded products…
VB: The legal regime that is foreseen, which is the Legislative Decree 8/2019 and that of Law 33/2018 [of 18 July], provides for the approval of Marketing Authorizations standard of some substances, in which a dossier is submitted and this assessment is then carried out. This is the national regime and, in fact, there is no harmonization at European level in this matter.

Yes, that is one of the questions. But couldn't it be done here like in Germany?
VB: Portuguese legislation only provides law along the lines of this decree, which is through the approval of an ACM, which offers a set of guarantees that the German system does not provide, obviously.

So that means they have to be pre-packaged…
VB: Yes, they must be pre-packaged, meaning there is no splitting at the pharmacy. The packaging is dispensed, upon medical prescription, to a patient who has one of the [seven] previously approved pathologies and is for a preparation or substance with an ACM. This is what Portuguese legislation provides – which is similar to many other laws, such as Canada, Israel or Denmark.

“When regulatory systems are demanding and rigorous, users only benefit. Of course there may be more constraints and more difficulties, but companies have to adapt.” —Vasco Bettencourt

Couldn't this issue be overcome by simplifying a little? In other words, follow a little what Germany does? Although it is not up to you to decide, it is up to you to comply with the law, but you work together…
VB: It is necessary to see that we here have the role of regulator. When the legislator decided to create this legislation – and Infarmed itself also contributed [to this legislation]… But what concerns us is the quality and safety of those substances. The marketing authorization system guarantees this quality and safety. Why? Because a substance can only have an ACM if it is manufactured in a manufacturer that has a manufacturing authorization – therefore, that complies with GMP standards [acronyms in English for Good Manufacturing Practices or Good Manufacturing Practices] – and, in turn, your plant supplier, if not yourself, must comply with GACP standards [Good Agricultural and Collecting Practices or Good Agricultural and Harvest Practices] — and all of this is verified when analyzing the ACM application dossier. In addition, a set of other issues are mentioned that are defined in DL 8/2019 itself and also apply subsidiarily to the Guidelines do Herbal Medicines, in which there is a set of rules that must be respected to guarantee the homogeneity of the product. There has to be some guarantee of quality and safety of systems that have to be reproducible. There must be this security for users. And now let's try to balance: access or quality? At this stage, Infarmed, with the legislation it has, prioritizes both: quality, but with access. Now, companies have to adapt. Regulatory systems, if they are too lenient, everything is approved, but then at the end of the day, probably, the public health guarantee is not observed. When regulatory systems are demanding and rigorous, users only benefit. Of course, there may be more constraints and more difficulties, but companies have to adapt.

Ana Paula Martins during a presentation at PTMC – Portugal Medical Cannabis, in April 2023, at Quinta da Picanceira

But many users are losing out in this case. There are many people who need to treat themselves with oils and still do not have access to them. Perhaps this range of homogeneity is a guarantee, but is it necessary to reach this extreme? There are countries that do not have all these obligations and the system is not as demanding; and while we wait for companies to be able to comply and overcome all these bureaucratic and financial obstacles, the people who need them are suffering and many continue to turn to the illegal market. And that's where they don't have any guarantee of quality.
VB: I wouldn't call it bureaucratic. Bureaucratic is from the perspective of those who do not see their solution being resolved. But I can tell you that there are companies that have very high quality standards and others that have very… debatable quality standards. In fact, this process, compared to the approval of an AIM [Marketing Authorization] for a medicine, is extremely simplified. Now companies have to comply with the minimums. I give an example now in the activities: we have companies that comply with GMPs, we have companies that comply with GACPs, and we have companies that do not comply with either. And then we have companies that go far beyond what the regulator requires. This shows that, perhaps, companies that did not pass call them bureaucratic and extremely demanding, but those companies that go far beyond what is required, because those exist, may even consider that, perhaps, GACPs even lacked a review, because they fall far short of what our activity actually is.

“There are companies that have very high quality standards and others that have very… debatable quality standards” — Vasco Bettencourt

Yes, and wouldn't it be important to put things in perspective? We know that Infarmed plays its role and has to stick to what the law says. But people have been using this without any regulation, without quality control, for more than a hundred years... It's good that we have this control, this requirement, which is what the activists themselves have always defended: being able to access a quality product. But is it necessary to go that far? Couldn't Infarmed work with the legislator to simplify these processes, without sacrificing quality?
MPA: Giving up quality is a bit difficult.

No, we don't want to compromise on quality! We want to maintain quality, but wouldn't it be possible to increase the margin of maneuver?
MPA: Almost all of our medicines, and even those used to treat cancer and other diseases, came from plants and we have always used plants, but knowledge evolves. And we have to try to ensure that when people use a product, for example mint tea to ease digestion or anything else, they have a therapeutic indication and there are approved medicines, not here in Portugal, which I don't think anyone asked us for, but in other countries, but which guarantee these quality aspects. And regarding cannabis, it is a plant that has actually been used for a long time and we know that, but also, like other plants and other medicines, it has side effects, it has interactions, and if we don't have the levels well defined, at least the two main cannabinoids [THC and CBD], it becomes complicated. Besides, as I told you, we've already tried, well, to be a little more... it's not condescending, but we try to allow companies to be able to place their products on the market. Normally, for herbal medicines with constituents with known therapeutic activity, we allow a variation of plus or minus 5% in what they say. And for cannabis we are already reaching 20%, so we have already expanded a bit. But we can't go much further than that. Then [people are subjected to] having no effects, or the effects regressing or having other effects, which from a treatment point of view is not desirable.

At Quinta da Picanceira, Infarmed made three presentations on the licensing and inspection processes for medicinal cannabis. Photo: Renato Velasco | PTMC

A little while ago you said 10%, now you said 20%…
MPA: I said this because, normally, for all plants, what is allowed is a variation of 10%, and now we are reaching 20% ​​because in the monograph that is approved for the German pharmacopoeia there is a variation of more or less 10% in relation to the declared content. Therefore, plus or minus 10 up to a range of 20%, that is: if declared 20, it could be minus 10 or plus 10 – which already widens it a bit and allows some more room for maneuver for companies.

In the report on the evolution of the activity you have “number of entities: phase 1 and phase 2, without or with documentary aptitude”. What does this mean exactly?
VB: So, the licensing request, in the first phase, is documentary; the second phase is on the spot, with inspection of the facilities. Ah, here we have the “Pre-Decision Fitness Phase” and the “Post-Decision Fitness Phase”. Therefore, the Suitability Pre-decision Phase is where the request has been submitted with documents and is being evaluated. The Suitability Post-decision Phase is when the request, documented, was considered suitable, as a set of requirements were verified, those contained in the 83 / 2021 Ordinance [on April 15], where everything that needs to be checked is described. It then goes to SICAD [Service for Intervention in Addictive Behaviors and Addictions] to check the suitability of the applicants, the technical manager and the safety manager. And then, there is still circulation through various ministries – Agriculture, Economy, Justice, Internal Administration – and after having circulated through these ministries and there are no negative pronouncements — this does not mean that they are binding —, it moves forward. When it arrives at the ministries, everything is already very refined, because the process of requesting elements, the response to requests, has already been done by Infarmed and so when it reaches the ministries it is already in the final phase and ready to go. Therefore, from the outset there will be no constraints or unfavorable opinions to the process. After issuing this decision of documentary suitability by our Board of Directors, the company is notified and has six months to request an inspection of the facilities, which can be revoked two more times for the same period – that is, a total of one year and quite. If at the end of that year and a half, the company is still not in a position to request an inspection, it is still a possibility – and this happens to some companies where the installations are already being implemented, but are not yet finished, there is still the possibility of a new request for an extension until the completion of the works, when the company actually demonstrates that it is carrying out works on the ground.

“We are probably the country with the most requests submitted and with the greatest interest from multinational companies. If we were so bureaucratic, I don’t believe companies would go to Portugal” — Vasco Bettencourt

So what's the point of having deadlines?
VB: Because there are those companies that have the aptitude request and then go knocking on doors looking for investment to start the works and then reach the end of a year and say: “now we have found an investor”. And we say: “look, now it’s the deadline; So one of two things: either submit a new request, or else… because what often happens is that after a year and a half the request is already distorted in a certain way, that is, the investors are no longer the same, they are no longer the same. I would have to go to SICAD again, the project is no longer the one they had submitted, because new investors came in and had to change it a little. These deadline rules exist for these reasons, not just because they exist. And we count these six months in working days, so it's two years and so on. But if the company still doesn't have anything on the ground, then the process expires and you will have to submit a new request. If the company requests an inspection, it is carried out depending on the type of authorization requested: cultivation, manufacturing, import and export and marketing. If it is cultivation or manufacturing, see if it complies with GACPs; if it is manufacturing, it complies with GMPs. Importing and exporting always requires an ancillary authorization, it is not something that can be independent – ​​there is no one who can import or export without cultivation, manufacturing or marketing, which is wholesale, not retail.

Basically, is that what most companies based in Portugal do, cultivate and export?
VB – Companies based in Portugal cultivate and export, although, in a way, many companies are beginning to appear that are already in the post-aptitude decision phase, with a manufacturing aptitude decision. Therefore, in addition to cultivating and exporting, they also want to be able to manufacture.

In this case, it will be manufacturing to sell here, not just for export… And are the certificates given per product or to the company?
VB – It's by activity. It may be that manufacturing complies with good manufacturing practices for the substance up until the packaging of the dried flower, but those good manufacturing practices are for a different formula – for example, oils. Now, the certificate of good manufacturing practices specifies which pharmaceutical formula is made. In other words, if the factory is authorized for substances and later wants to make preparations, it will have to update the certificate.

So, for each product it wants to put on the market, the company has to go through the same process?
VB: No, it depends on the type of pharmaceutical form. If you are talking about dried flower with different levels, that GMP certificate is covered. But if for example, if in addition to the dried flower you want to include an oil…
MPA: Or two or three…
VB: … or two or three, then you will have to include this pharmaceutical form of extraction.
MPA: … of extraction and, essentially, of preparing the pharmaceutical formula, which is an oral solution.
VB: Oral solution, ready. And then you will have to update. Because although these are good manufacturing practices, there are certain standards or specificities that must be observed and the GMP verification of dried flower will not eliminate the evaluation of other types of operations that wish to be carried out that are completely different.

And in terms of ACM for each product…
VB: Yes, they are two different things. One thing is for products and another is for company activities. A company, which may even be a cultivator, that wishes to submit an ACM, must, in its dossier, demonstrate that the product was produced by a manufacturer with a GMP certificate for that type of substance/preparation and that the product, that is, the plant, originates from a supplier that also complies with good agricultural and harvesting practices [GACP].

“We think it is important that patients, in fact, have flowers and oils of different levels to use for various pathologies” — Ana Paula Martins

And you say it’s not a lot of bureaucracy…? (laughter)
VB: No, it's not. It's bureaucracy, perhaps, to realize it suddenly (laughs). But it is not. In fact, fortunately, at an international level, we have been widely referred to as being a regulatory agency that puts what is required in very black and white. And proof of this is that we are probably the country with the most requests submitted and with the greatest interest from multinational companies. If we were so bureaucratic, I don't believe companies would go to Portugal.

It depends on the companies... some will have the structure for this and others won't, and in this aspect it becomes quite selective, doesn't it?
VB: But structure in what aspect?

So, it has structure: human and financial capacity to be able to undergo all these steps, conditions, and the investment that needs to be made.
MPA: Yes, but remember, the pharmaceutical industry has to have this capacity for this type of investment and [cannabis] until now was not [considered a medicine], but now it is and, therefore, there have to be people who understand the issues regulatory. Sometimes I get questions from people who don't understand anything and want to get involved in an ACM. We are happy to help, but these people have to hire the services of someone who understands these regulatory issues who can help them, because, in fact, it will not be a farmer, who has never placed an order for a medicine, who can understand the complexity of medicine legislation.

“This argument that only multinationals can do it, I don’t think it’s valid. We have numerous entities that have already reached the stage of deciding whether to have documents that are Portuguese micro-enterprises” — Vasco Bettencourt

Yes, but we run the risk of falling into what is happening in the USA with what are called legacy growers, that is, people who have been cultivating and working with cannabis for a long time, who have already prepared products for medicinal purposes, who even have a stable product and have patients to whom they supply regularly for years, and who end up being left out because they do not have ability to face all of this.
VB: But allow me to disagree. We have micro-enterprises with reduced financial capacity, with very small areas, that submitted requests and had their GACP requests approved. So this argument that only multinationals can do it, I don't think it's valid. It may be an argument that people try to cling to, but we have countless – countless – entities that have already reached the stage of deciding whether to have documents, which are Portuguese micro-enterprises. We had one in the south of the country, whose area was perhaps 200 m2 in area, and it managed to comply. In fact, it's curious, because multinationals bring the know-how of multinationals, but the technicians are all Portuguese – we do not have foreign technical managers, they are all Portuguese. Just go to the list of companies that are licensed and see. Therefore, of course, multinationals came to imitate what they had in their countries of origin and in the structures they already had created – obviously this makes it easier –, but we cannot see that… An example: Terra Verde [today Curaleaf] was, in 2014 , the first company [to establish itself in Portugal]. Although it was held by Israelis, the critical mass was entirely Portuguese and consisted of greenhouses. They produced the raw material for a medicine, I don't know if Sativex or Epidyolex, because they supplied GW [Pharmaceuticals], but the idea that only multinationals have the capacity to meet the demands that the regulatory authority places is not true . In fact, proof of this is that we have Spain, which is a country seven, eight, nine times larger than ours, and has this much more incipient area, compared to ours...

Yes, but Spain is a particular case.
VB: We all have particular situations (laughs).

No, but in the context of the legalization of medical cannabis…
VB: But do you think that the legalization of medical cannabis didn’t work either…? Let's see something: Law 33/2018 is from 2018. In 2017, we already had 10 companies in the licensing process. It was before the legislation, it has nothing to do with legalization. Legislation has always made it possible, in fact, we have United Nations conventions, they have never prevented the use of cannabis for medicinal purposes.

“Infarmed’s objective is public health. Our ultimate objective is that these companies, in addition to choosing Portugal to carry out their operations, are able to produce a quality product, which is not only intended for export”. —Vasco Bettencourt

But they make it very difficult to access raw materials to be able to carry out clinical trials and tests. It was one of the things that scientists had complained about all these years. If the raw material or substance is prohibited, how could you have access to it? There are even funny stories about this, about scientists who had to go and buy despite the law [Raphael Mechoulam, had to ask the police himself]. But anyway, this is also in line with what we were talking about a moment ago: the labor is Portuguese, but because it is qualified and cheap. Therefore, even if companies did not want to order any AMC here or sell anything in Portugal, they are interested in establishing themselves here to cultivate and export. In other words, they are different things that do not necessarily benefit Portuguese patients.
VB: I have my own opinion about this... I wouldn't go to the pictures that those who come to Portugal do so because the labor is cheap, the land is cheap, the energy is cheap – most companies in Portugal do indoor, grows in greenhouses, with lights – so I wouldn't go there. I think one of the factors was the clear way in which regulatory rules exist in Portugal. Why can we say this? Because when we started working on our legislation and regulations, it was not clear in practically any country. There was Canada, which, in fact, had it; Israel, in a different model, also had it; and the case of Denmark, which was also growing with a pilot project. But everything else didn't exist. Therefore, what Portugal brought was clarity in terms of regulation. Now is it bureaucratic? If it were, we wouldn't be receiving almost... how many companies? So, with documentation skills we have 150 companies. To give you an idea: the wholesale distribution of medicines in Portugal involves around 400 companies and is a sector that has existed forever... And cannabis arrived and managed, in fact, to gain space, and thank goodness, because on the one hand It created jobs, not only for those [companies] that are already operating, but also indirect jobs for all those companies that are creating the conditions to start operating, even if they don't come to fruition. Now, Infarmed's objective is public health. Our ultimate objective is that these companies, in addition to having chosen Portugal to carry out their operations, are able to produce a quality product, which is not only intended for export – because a large part of the export is not finished product, it is dried flower, but sold in bulk, it is raw material to be processed elsewhere. Therefore, the objective – and this is a path that is being built – is to manufacture quality products and that these products can have an ACM and be available to our users, to our patients. That is our main objective.

There is a significant increase in the number of entities [that requested licensing], from 3 in 2017 to 75 in 2021; but then in 2022 there was a decline [to 19]. Why do you think this happened?
VB: There are fewer orders coming in.

But why? What is your reading?
MPA: I don't know, I believe the situation is at an international level. There was a lack of definition, many companies had problems, many closed, they are laying off workers, so perhaps companies expected to have a much faster return on investment and that is not happening. Several companies in Canada had to be restructured and in Israel too, I believe.
VB: There is also another factor: this peak that occurs in 2021, it seems to me that, as in any activity, it tends to stabilize afterwards. Because what we see is that most of the companies that exist, multinationals and some Portuguese, came into force in 2019, 2020 and 2021 and then there is always a downward curve. It is not expected that there will be many more to be created. Still, in 2022, [licensing requests] continue to come in and in 2023 as well. We have had an average of one order per month. But there is a job here that people never see and that is changes. It's funny when they think “oh, you're licensed, that's the end of it”, but you get licensed today and tomorrow they want to change something to the initial request. In other words: what is counted is the number of requests entered, we are not counting the number of requests for changes to the requests entered.

“We have to know the companies’ partners and we have to know the company. Why is this? Because we don’t want to have people here with criminal records of drug trafficking in this area” – Vasco Bettencourt

And are there many?
VB: Change requests? They are immense. Incoming orders triple. It's very simple: a company makes a decision on suitability with a group of partners, then considers that it needs another partner to come in who has the capital to build something, or already had the expectation, after having made the decision, to raise money. some more investment, and will submit a request to change the composition of the company that is here. We have to know the companies’ partners and we have to know the company. Why is this? Because we don't want to have people here with criminal records of drug trafficking in this area, therefore, we have to carry out this very strict scrutiny. And this is an example. Or let's suppose: the company initially had a plant, but in the post-aptitude decision it thinks “we don't have the capacity to support it, the market is changing, we're going to halve the area of ​​the facilities”, and there is a new order change to the initial one. So, as you can imagine, this is completely dynamic: orders are dynamic, just as companies are dynamic. So, in an area that is constantly changing, when news comes out and it is exponentiated to the maximum and then you come to the conclusion that it wasn't quite that, that's it, it also ends up generating a lot of dynamics and a lot of volatility.

Of course, it is a complex and volatile market and companies are living organisms…
VB: That's right. It's just to convey that this happens.
MPA: We have a large international company that invested a lot and then decided it was better to close.
VB: It decided to close and probably continued operations elsewhere.

Yes, that happens too. Another reason we hear from companies entering this market is that the investment is so large that it is difficult to sustain the time that all these processes take. But well, in relation to the sale of substances and preparations, do you think they could be sold not only in pharmacies, but also based on a dispensary model as already exists in other countries, or even in cannabis stores?
VB – We cannot give an opinion on this. This is a change that has to go through the Assembly of the Republic.
MPA: The 2018 Law says that cannabis for medicinal purposes can be used when normal treatments are not working or have very serious side effects, and with a medical prescription, therefore it would have to move to a dispensation scheme... or not be mandatory to recipes.

Couldn't these spaces accept prescriptions for this specific type of substance?
MPA: This would imply a major change that has to be initiated in the Assembly of the Republic.

“If people who have no other solution can improve and feel some significant change in their quality of life, even if they are not cured, and if doctors monitor and validate this improvement, I think, clearly, people should be able to access [to cannabis]” — Ana Paula Martins

But as a medicine regulatory entity, do you consider that it could be a viable option to not have to go through pharmacies?
VB: We currently have no opinion on this. It always had to originate from a law of the Assembly of the Republic, because there are several factors that would have to be taken into consideration. There would have to be a big discussion, with all partners... Because the medicine and medical device circuit, as it exists – because it exists, it is created – would require the creation of an entity that falls outside the medicine circuit. I don't know, it was an issue to be discussed. Furthermore, to distribute a medicinal preparation, which is almost equivalent to a medicine, only pharmacies can dispense medicines, therefore…
MPA: No, there are over-the-counter medications.
VB: Ah, yes, but that was yet another operation. It meant no longer having a prescription and becoming over-the-counter, that's it. But I wasn't even going there anymore.

In terms of medicinal cannabis, being available over the counter is more difficult and that is not how it would be possible to guarantee adequate treatment for patients. It would just be about expanding the network of sellers.
VB - Of course. But there are more than 2803 pharmacies in the country, in mainland Portugal.

Yes, there is no shortage of pharmacies.
VB: It's something that's not missing. Therefore the secure network is in place. Pharmacies are supplied by distributors and manufacturers who are also controlled and regulated, which is why, when we arrive at the pharmacy, we are completely sure that the medicines we are going to purchase are controlled medicines. We never question that. We already take it for granted.

The reason for my question is because, given the specificity of cannabis, a very close (and important) relationship is normally established between those who serve and those who buy. There is this human side of knowing the particular needs of patients, and knowing the product very well [in dispensaries]; while in pharmacies there is a colder environment and they are less knowledgeable about the plant. It's a slightly different model...
VB: There needs to be a discussion with all those involved in the health sector, civil society, because this has implications.

Medical cannabis products tend to be quite expensive and many patients will have difficulty meeting their needs, running the risk of continuing to turn to the illegal market. Should or could products be reimbursed?
MPA: This matter lacks legal provision and will have to be assessed within this context.

And do you think cannabis is a realistic solution in medicinal terms or is it too complex to be truly implemented and used as a medicine?
MPA: From a scientific point of view, obviously it can be. But like many things, we still know very little and a lot of research needs to be done. From my point of view, if people who have no other solution can improve and feel some significant change in their quality of life, even if they are not cured; and if doctors monitor and validate this improvement, I think people should clearly be able to access it. Cannabis really has an effect on our CB1 and CB2 receptors, it certainly has many effects that can be used – whether as an extract or as isolated constituents. Cannabis produces more than 100 different cannabinoids, probably several of which could have a very interesting effect on some pathology. Much more research will certainly be needed to prove these effects and the action on the endocannabinoid system, which is a difficult system to balance and which, when disturbed, can have some serious complications, as seen with the use of some endocannabinoid antagonists. endocannabinoid receptors.

Again, for you as regulators, is it viable? Because there may be countless products with different proportions of cannabinoids. Does Infarmed have the structure to deal with this?
MPA: Having more than 100 chemicals, with so many levels, it is difficult to validate their use. But at the moment, it's hard to say.