1) Requirements for clinical trials
The Vietnam national legislative documents indicate that a foreign drug for which qualified safety and efficacy assessments from clinical trials are available - regardless of where the clinical trials were conducted - and has been accepted for sale in at least one country can be considered for circulation in Vietnam (19,20). However, most interview respondents were not aware of these procedures and assumed that results from clinical trials in Vietnam are necessary for a drug to be granted a license in the country. The respondents were concerned that the efficacy and safety data collected outside Vietnam would not convince those who influence malaria policy in the country. To support their claim, interviewees referred to the introduction of PA in Vietnam. Before PA was used in the NMP from 2019, it was tested in several provinces in the Central Highlands of Vietnam despite the published results of international clinical trials for PA since 2008 (21,22).
Normally, the pioneers must evaluate the efficacy and safety of this drug in Vietnam. Because later, according to the current process, the drugs are said to be effective somewhere over, people do not care, when it is introduced in Vietnam, there must still be a trial and evaluation of safety, efficacy, and safety of that drug in Vietnamese patients … The clinical trial is a must. The good results from this will be the basis for the (national malaria) program to propose for implementation of the malaria treatment… (Representative of NMP)
So, to put it in Vietnam, we need to have a protocol, even though it has been assessed in many research places, but when it is introduced into Vietnam, it still needs a re-assessment. (Representative of NGO)
In Vietnam, clinical trial proposals must be reviewed by the MoH’s Scientific and Ethical Committee before commencement. Trials must be implemented in compliance with the approved proposal and Good Clinical Practices (GCP) recognized by the MoH, such as International Council for Harmonization of Technical Requirements for Pharmaceuticals for Human Use - Guideline for Good Clinical Practice (ICH-GCP) or WHO-GCP. Clinical trials require a pre-determined sample size. P. falciparum cases in Vietnam have been steadily decreasing for the last few years highlighting challenges in recruiting a sufficient number of patients into a malaria drug trial. Nevertheless, some respondents suggested it might be possible to organize and conduct trials for TACTs in Vietnam.
I think it is possible. Well, if they take the sample size fluctuating between 49 and 61 cases, maybe we can do it…In fact, in Vietnam, given the current situation, we can conduct a clinical trial in areas of Gia Lai [a province of Central Highland in Vietnam], where the number of cases is very high. We can conduct within two years. We can have enough sample size to compare between the current regimen, which is Pyramax, and the three-drug regimen [TACT]. (Representative of NGO)
2) Requirements for drug registration
Agencies with a Certificate of Eligibility for Pharmacy Business, which permits manufacture, wholesale, export or import of drug/medicinal material, can register drug’s certificates of free sale in Vietnam (19,20). The respondents expressed their concerns about the low motivation of agencies to introduce a new antimalarial given the small market size as Vietnam. They referred to an incentive asymmetry between investment on research, manufacturing, advertising, and regulation while potential profits are limited. This was given as the major reason why domestic manufacturing of antimalarials in Vietnam has stopped. However, few respondents believed that manufacturers would be interested in manufacturing or investing in TACTs for corporate social responsibility than for profit.
But in some cases, pharmaceutical companies still do it for the social responsibility to prevent malaria, to eliminate malaria for the community, they could still do it. (Representative of NMP)
Besides such benefits, it will specially lead them to new type of therapy that benefit the patients, the new therapy is more effective than the existing one. (Representative of International Pharmaceutical Company)
For a new drug to be freely distributed, a comprehensive and standardized dossier that includes administrative and technical components, must be submitted to DAV for a certificate. The administrative component refers to application forms, legal documents of the agency and the imported drug. Technical documents are required to have pre-clinical and clinical documents with sufficient data for analysis and justification of influence of Asian racial factors on the safety and efficacy of the drug in order to extrapolate clinical data on the Asian populations. These documents must conform with guidelines given by ICH, the MoH of Vietnam or other organizations recognized by Vietnam (20). Furthermore, a drug with a new combination of active pharmaceutical ingredients (eg. TACTs) must have sufficient clinical data according to guidelines of United States Food and Drug Administration (FDA), European Medicines Agency (EMA) (23,24)or WHO for clinical development of fixed-dose combination drugs. The application often takes several months to prepare.
The minister of Health can issue a certificate of free sale upon consultancy of the advisory council based on the results of the application assessment. This assessment procedure is coordinated by the DAV. The process can take up to several years to complete, especially when the application needs to be revised and re-submitted multiple times to address questions or concerns on new active ingredients, combination of more than two active ingredients, or indications of serious or frequent side effects. Therefore, well-prepared applications by experienced companies and strict adherence to official guidelines was recommended by experts when submitting TACT dossiers.
A few additional barriers have recently delayed the approval process for new drugs. The first is the temporary shortage of personnel at the DAV and experts participating in the review councils. Therefore, there are many pending applications on DAV’s waiting list. Second, there are many new registrations every year, and each application adds to the waiting list. Third, although the MoH has outlined a roadmap to digitalize the drug registration application, which allows online submission of dossiers, the system has not been implemented yet. The manual management and processing of applications leads to a significant increase in workload of the scarce personnel and further increases application time.
Another challenge is that the applications are still in paper-based, so they are piled up in the DAV. When I went to work there, I felt overwhelmed with a lot of files around. Therefore, lost files or papers are possibly very high. And I had experiences in lost files twice. And if your files in application are lost, you will have to start over and submit as the beginning. (Representative of International Pharmaceutical Company)
Contrary to legislative documents that indicate a 12-month timespan for a drug’s certificate of free distribution to be issued upon application, it can take up to several years before a drug is approved, as experienced by some respondents.
The manufacturer has started the drug registration process since 2019, the application has been submitted to the DAV, but until now, after 3 years, it has not received approval yet. Meanwhile, Tafenoquine has been one of the drugs in the list of ASEAN's Join-review program to speed up the approval process and is prioritized for approval. (Representative of NGO)
The procedure of registration of a new drug in Vietnam could be shortened if the drugs are eligible for quick and simplified validation of registration for free distribution. There are indeed some drugs (e.g. PA for P. falciparum treatment or antiretroviral drugs for HIV treatment) that have been licensed for import, to use in Vietnam with a specified quantity without registration for certificate of free distribution, because a) it serves a national health program, b) it is used as humanitarian aid priority, or c) because it is to be used for other non-commercial purposes as stated in current Vietnamese pharmaceutical law. If TACTs go through the routine drug approval procedures, it will likely not be possible to deploy TACTs on time. Therefore, some respondents suggested to apply for a simplified validation of registration or an import permit without registration for TACTs.
3) Inclusion in national treatment guidelines
Monitoring and revision of national malaria treatment guidelines is the responsibility of the NMP. Consideration of including a new drug in the treatment guidelines typically is derived from recommendations of the WHO or regional and global policy makers and aims to respond to situations of resistance or reduced effectiveness of current drugs in the country. The NMP will gather experts from the institutes, clinicians from national hospitals, scientists, other stakeholders and WHO representatives in Vietnam to consider options from the list recommended by the WHO, clinical trial data, drug availability and economic efficiency. The draft of new guidelines is developed by the NMP based on consultation of experts at central and local levels and then reviewed and approved by The MoH (25).
The administrative procedures take 3 to 4 months for new guidelines to be approved by the MoH upon submission of final draft. However, the timeline for consideration and development of the final draft can take up to a year.
Factors that are highly persuasive to malaria policy makers in Vietnam for the introduction of new treatment policies is evidence of resistance to current drugs and strong evidence of safety and efficacy of the new proposed drug. Additionally, recommendation by the WHO, achieving WHO prequalification status, approval by Australia Therapeutic Goods Administration (TGA) or US FDA are considered important enablers. Policymakers would consider drugs that are licensed by the Ministry of Health, commercially available, low-cost, and accepted by the donor. Respondents stated that facilitating the communication between policymakers, pharmaceutical company and donors is important to promote the introduction of a drug. Activities carried out by NGOs for promotion of tafenoquine were highlighted.
Firstly, providing information to experts in Vietnam, such as the results of scientific research, the results of clinical trials. Secondly, providing the experts here or the decision-makers information to let them know about, for example, how the process of Tafenoquine approval in other countries was like. Then providing information about the process that is called PQ approval, such as process of WHO Prequalification approval. As we have involved in some Global projects, for example, they have got some connections with the World Health Organization so that we could understand the processes of submission and approval for introducing the guidelines of the World Health Organization… organized big seminars to provide information for both sides. For policy makers and health workers, they paid attention to the cost, the approval of drug use in Vietnam. To the manufacturer, our project also conducted seminars for them so that the manufacturer could realize the need of the drug in Vietnam. (Representative of NGO)
Almost all respondents indicated that it would not be challenging for TACTs to be included in national guidelines if its safety and efficacy can be demonstrated through clinical data collected in Vietnam, and if it is included in the WHO antimalarial treatment guidelines.
4) Changing antimalarial treatment policy
Systematic training of trainers will need to be conducted from the central to community level because malaria treatment mainly takes place at community health stations. Comprehensive training must be organized for hospitals and preventive facilities in order to have sound understanding of new treatments including adverse events and how to handle them. The NMP prioritizes the training in provinces with high malaria prevalence first, and then in provinces with risk of imported malaria cases. The training is available digitally through public guidelines or as video content.
I don't think it challenges. It only requires human resources from three Institutes [NIMPE, IMPE in Ho Chi Minh and Quy Nhon cities], who will conduct trainings for the provinces, then the provinces themselves will train down to the lower levels like that (Representative of NMP)
New therapies such as TACTs were expected to be easily accepted by prescribers and patients if it is convenient to use as a single dose per day for a short period, available as a fixed dose combination, and with no adverse effects. Surveillance of adverse effects will be based on national drug information and adverse drug reaction system (26) and NMP’s surveillance systems.
5) The current need for new malaria treatment therapies
As indicated in interviews, DHA-PPQ was widely used in recent years in provinces where evidence of drug resistance has not been detected. DHA-PPQ has been replaced by PA in 4 provinces with high rate of resistance from 2020. PA is now commonly used because, contrary to most alternative ACTs, it has high efficacy (1,11) and is now available through external funds. Although treatment guidelines have not yet been revised, many national program leaders consider PA to be the first-line treatment for malaria. They plan to change this guideline in the near future.
After the combination of DHA-PPQ, the National Malaria Program and the World Health Organization [Representative in Vietnam] had meetings and decided to change the antimalarial from DHA-PPQ to use a combination called Pyramax [PA], as you probably know, Pyramax has been used for 2 recent years… In the near future, it is likely that new documents, new regulations will be issued. (Representative of NMP)
Respondents confirmed their awareness of the emergence and spread of artemisinin resistance in Vietnam, but the situation was considered somewhat more positive than in other countries in the region. The treatment failure rate with DHA-PPQ reached up to 60%, which was also confirmed by recent therapeutic efficacy studies (27,28). Artesunate–mefloquine is currently not widely used in the NMP. According to the Annual Report of NMP for 2022, the day 3 positivity was 40% after treatment with artesunate–mefloquine (1).
Many respondents were confident about the efficacy of the newly introduced treatment, PA, and expected to rely on current ACTs until P. falciparum malaria elimination would be achieved. They perceived that introduction of new treatment at this stage is not an urgent necessity. They also referred to the fact that there have not been any new treatment policies for P. falciparum recommended by the WHO other than current ACTs.
It is important to note that now, PA is the only treatment available for P. falciparum in Vietnam. PA is procured internationally by The Global Fund to Fight AIDS, Tuberculosis and Malaria and provided to the countries in the region. Respondents emphasized that this is important because self-procurement of a small quantity of drugs for diminishing treatment needs would be challenging for these countries, as emphasized by respondents. Therefore, in the future, if bordering countries of Cambodia and Lao PDR change their treatment policies due to the spread of drug resistance in these countries, Vietnam would need to consider accordingly.
6) Timeline to introduce TACT and malaria elimination target
Although Vietnam is making good progress towards the target of eliminating P. falciparum by 2025, some respondents were not optimistic that Vietnam can accomplish this target within the time frame because they believed that the last cases would be the hardest to eliminate. If P. falciparum elimination is achieved by 2025, this would be before the prospected market introduction of TACTs.
To introduce any drug into a market like that will be, will be quite difficult, very time – consuming and it may take a few years so it might be that the introduction process is not finished but the program is already, already [laughter] over. (Representative of NGO)
it seems impossible to do that [malaria elimination] so in a few, a few years, by around 2025–2026 (Representative of NGO)
The respondents were concerned that resistance to the newly introduced PA may emerge in the next few years although it is currently effective. They cited concerns related to the movement of mobile migrant population among countries in the Greater Mekong Subregion leading to the spread of drug resistance, and the drug pressure on PA when it becomes the only treatment choice in the countries. Therefore, the respondents prefer access to alternative treatments as a backup if PA starts to fail or if there is a resurgence after elimination is achieved (29). They indicated that to their knowledge there are no new drug compounds expected on the market within the next years, and therefore TACTs would be useful because they can be deployed rapidly (13). Interview respondents agreed that moving towards introducing TACTs would require timely preparation of procedures.
But we only give one kind of drug (PA) for those 200 cases, then, the pressure of the drug on the population of parasites that already has multi-resistance. Therefore, the likelihood of resistance now is much higher than in the past (Representative of NGO)
So, if the efficacy of the current drug decreases faster than they expected, they must have another one to cover. So, I think now is the time to introduce it, not so that it can be used immediately, but for the time we need to prepare the necessary procedures and works before it can officially be used. (Representative of NGO)
Other respondents indicated that TACTs should be used in the country as soon as possible to support the P. falciparum elimination target.
TACT is a, a very sharp knife for the current situation of drug resistance in Vietnam and also in the region. It’s an alternative that’s worth paying attention to and following and should be put in use as soon as possible so we can, can manage immediately any case detected. That is, to eliminate it, to not let it reoccur and spread out, otherwise it would be more difficult to control. So, I think that in term of treatment, case-by-case treatment is very necessary these days. (Representative of NGO)
Indeed, to allow for TACTs’ full potential in preventing drug resistance, TACT would ideally be deployed even in settings where ACTs remain efficacious (13,15). This is demonstrated through recent mathematical modelling studies predicting that switching to TACTs could substantially delay the emergence and evolution of artemisinin-resistant alleles and reduce treatment failures (16).
Limitations of the study
Selection of respondents occurred in close collaboration with NIMPE. Nevertheless, it is possible that some important stakeholders with different perspectives were not included. Interviews were conducted in local languages and translated into English; hence translation bias could have occurred. The desk review was limited the documents that can be found through internet search when quite a few program documents from NMP were unable to access.