The use of special approval medicines among pediatric patients in a tertiary care hospital: A reality check

Abstract

Background

Special approval medicines (SAMs) are medicines used with approval from the Director General of Health Malaysia when the therapeutic options within regulatory and formulary boundaries appear unsuitable or ineffective to treat the patients.

Objectives

To examine and characterize the use of SAMs among children in a Malaysian tertiary care hospital.

Methods

The named-patient basis SAM application forms, cover letter, pharmacist review summary and patient monitoring forms available at the Pharmacy Department between 1st January 2019 and 31st December 2020 were reviewed. Unprocessed, unapproved and stock-basis applications were excluded. The outcome measures were categories, scope, off-label use and cost of SAM. Per-patient data were analyzed descriptively.

Results

Overall, 1010 patients (mean age of 8.7 ± 5.6 years) were involved in 328 SAMs applications. The most common SAMs pharmacological groups were nervous system (n = 371, 36.7%) and antineoplastic and immunomodulating agents (n = 332, 32.9%). Top three SAMs were melatonin (11.5%), scopolamine (7.6%) and cholecalciferol (7.1%). A total of 837 (82.9%) and 513 (50.8%) patients were involved in the SAMs applications for non-formulary and unregistered medicines, respectively. Unregistered, non-formulary medicines were applied for 47.3% (n = 478) of the patients. The majority of the scope for SAMs (64.7%) were to substitute the available alternatives in the national formulary which were ineffective or sub-optimal for the patients. Among the 262 patients with repeat applications, 93.8% reported disease or symptom improvement while 1.9% experienced side effects. Up to 17% of SAMs analyzed in this study were used for off-label indications. The total cost of the SAMs was RM8,748,358.38 (USD 2,090,418.86).

Conclusion

The use of SAMs among children in this hospital involved unregistered, non-formulary medicines used to substitute the available alternatives in the formulary. A concerted effort is warranted in exploring supplementary mechanisms to enhance the medicine registration process and formulary system towards facilitating enhanced provision of treatment for children.

1. Introduction

In most countries, the choice of medicines used to treat a disease is often ‘controlled’ by the registration status of the medicine and formulary system. However, the use of unregistered and non-formulary medicines are sometimes the cornerstone in the management of certain diseases^1,2 or population.^3,4 Furthermore, off-label use of registered, unregistered or non-formulary medicines is another spectrum of concern, especially in pediatric patients.⁵ Pediatric patients are prescribed with an average of 2 to 5 medicines per prescription,^6,7 which may increase up to 7 and 12 medicines per prescription for terminally-ill patients⁸ and patients in tertiary care centres,⁴ respectively. When treating pediatric patients, prescribers tend to use therapeutic options outside regulatory and formulary boundaries as the existing alternative is unsuitable or ineffective to principally treat their patients.^9,10 The problems with access to and supply of unregistered or non-formulary medicines is potentially a barrier in providing optimal care for patients.^11,12

It was reported that 22% of pediatric patients admitted for highly specialised inpatient care were prescribed with unregistered medicines.³ Various mechanisms exist in different countries to allow the importation and use of unregistered medicines for patient's use. In Singapore, the Health Sciences Authority (HSA) allows the importation or supply of unregistered medicines for patient's use as named-patient or buffer stock application via the Special Access Route (SAR).¹³ Similarly in Australia, the Special Access Scheme (SAS) allows for the importation and supply of an unregistered medicine for an individual patient under the supervision of a medical practitioner, on a case-by-case basis.¹⁴ On the other hand, a ‘single permit for import of drug’ can be applied from the Ministry of Public Health of the People's Republic of China for import of medicines without import registration certificates.¹⁵ Although some variations exist in these mechanisms, the ultimate goal remains unanimous to ensure safety, efficacy and quality of the therapeutic options bypassing the medicine registration regulatory pathways.

The use of non-formulary medicines have been reported worldwide in previous studies^16,17 whereby up to 20% of hospitalised patients were prescribed non-formulary medicines.¹⁸ In children, non-formulary medicines accounted for 13.4% of the total prescriptions, mostly for patients in the general pediatric wards.⁴ Non-formulary medicines were prescribed when conventional therapies have failed² or patients developed adverse reactions towards medicines within the formulary.¹⁶ However, the provision of non-formulary medicines in the hospital setting has been shown to incur additional pharmacy cost.¹⁹

In some situations, registered and formulary medicines are used for unapproved indications, commonly known as unlicensed or off-label use of medicines. The use of unlicensed or off-label medicines is common in the pediatric population, especially in oncology and critical care settings.^4,5 This is attributable to the greatly limited availability in the number of pharmaceutical dosage forms and the lack of scientific evidence for choices of medicines in the pediatric population.⁴ Furthermore, the lack of clinical trials in the pediatric settings as a result of the high heterogeneity in pharmacokinetic parameters as well as the ethical and legal issues for research have also contributed to the unlicensed and off-label use of medicines among this group of patients.^20,21 Consequently, unlicensed and off-label medicines are used as first-line agents to treat pediatric patients.

In Malaysia, the National Pharmaceutical Regulatory Agency (NPRA) is a regulatory body which is responsible to register medicines which has fulfilled the registration requirements determined by the Drug Control Authority (DCA). In line with the objective of the Malaysian National Medicines Policy (MNMP),²² the Ministry of Health Medicines Formulary (MOHMF) serves as a reference to medicine prescribing in the Ministry of Health (MOH) facilities by emphasizing on the priority of using registered medicines to promote equitable access to safe, effective and good quality medicines. However, the usage of medicines outside the MOHMF (hereinafter referred to as non-formulary medicines) or unregistered medicines are allowed, in justified circumstances, with special approval from the Director General of Health Malaysia, Senior Director of Pharmaceutical Services, Director of Pharmacy Practice and Development, Hospital Directors or Family Medicine Specialists (FMS) in-charge of Health Clinics. This group of medicines are known as Special Approval Medicines (SAMs). Generally, SAMs in Malaysia comprise of non-formulary medicines, medicines within the MOHMF used for off-label indications, and unregistered medicines. Overall, the approval for and total cost of SAM in MOH facilities showed a three-fold increase from the year 2016 to 2020.²³ Most of the approved SAMs from the year 2016 to 2020 were non-formulary registered medicines, with about 41% in the year 2020 attributed to unregistered medicines.²³

Although the use of unregistered, non-formulary and off-label medicines in pediatric patients appears inevitable, it was reported to be inappropriate in some cases,²⁴ had a potential for interactions⁴ and significantly higher risk of adverse drug reactions (ADR),²⁵ urging the need to examine the use of these medicines in hospital settings. To the best of our knowledge, there are no studies examining the use of SAM in Malaysia, leading to scarcity of information on the use of SAM particularly in pediatric patients. Hence, this study was conducted to characterize the use of and identify the scope of SAM at a tertiary care children hospital in Malaysia. The data will be of paramount importance to healthcare policy makers for decision-making in the inclusion of medicines in the MOHMF in the future and to explore alternative mechanisms enabling access and supply of SAM in the country.

2. Methods

2.1. Ethical consideration

The study was approved by the ethics committee for Ministry of Health (MOH) facilities in Malaysia, Medical Research and Ethics Committee (MREC) (NMRR-21-738-59630). Approval to conduct the study was obtained from the hospital director and the head of department. The patient identifiers were kept confidential. The study was reported according to the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE)²⁶ recommendations.

2.2. Operational definitions

• a.
  Special approval medicine (SAMs) are medicines used in the MOH facilities with special approval from the Director General of Health Malaysia, Senior Director of Pharmaceutical Services, Director of Pharmacy Practice and Development, Hospital Directors or FMS in-charge of Health Clinics. These medicines include:

  • i.
    Registered, non-formulary medicines
  • ii.
    Registered, formulary medicines used for indications outside those approved by the DCA or MOHMF
  • iii.
    Unregistered, formulary medicines
  • iv.
    Unregistered, non-formulary medicines.

• b.A registered medicine is a medicine that is approved by the DCA for sale or use in Malaysia.²⁷

2.3. Study design and setting

The conceptualisation of the study was done through mapping of key terms, definitions and constructs of SAM application (Fig. 1). The cross-sectional retrospective study was conducted in a tertiary care hospital in the central region of Peninsular Malaysia. The 600-bedded hospital functions as the national referral centre and Centre of Excellence for women's and children's disease.

Fig. 1.

Conceptual framework of the study.

DCA = Drug Control Authority; DG = Director General; FMS=Family Medicine Specialist; MOHMF = Ministry of Health Medicines Formulary.

2.4. Eligibility criteria

Named-patient basis SAM applications for patients below 19 years old, received by the Pharmacy Department between 1st January 2019 and 31st December 2020 were included. Additionally, SAM applications for patients above 18 years old who were still under the care of pediatricians were also included. Unprocessed, unapproved and stock-basis SAM applications was excluded from the study.

2.5. Sample size estimation

The hospital formulary is a subset of the MOHMF. The total number of medicines available in the hospital formulary was 1219 items (according to the list updated on the 28th May 2020). Out of this, a total of 161 medicines were SAMs. The Pharmacy Department received an average of 150 SAM applications per year. Therefore, the estimated number of SAMs application during the 2-year study duration was 300.

2.6. Data collection

The study source documents were the SAM application forms, cover letter provided by the applicant, pharmacist review summary, patients monitoring forms and SAM approval documents. A structured and piloted data collection form was used to collect patients' demographic data, SAM details, SAM application details, cost of SAM and category as well as the scope of use of SAM.

The SAMs were classified according to the World Health Organization (WHO) Anatomical Therapeutic Chemical (ATC) classification. In the absence of exact WHO ATC classification for a particular SAM, the pharmacological grouping was made based on the routes of administration with clearly different therapeutic uses which were verified in discussion with the respective pediatric specialists. All SAMs except unregistered and non-formulary medicines were examined for its off-label use. A SAM was considered used in an off-label manner if the indication of the medicine were outside those approved by the DCA or MOHMF. The off-label categories were classified as:

• i.Off-label DCA: SAM used outside the indication approved by the DCA
• ii.Off-label MOHMF: SAM used outside the indication listed in the MOHMF
• iii.Off-label DCA and MOHMF: SAM used outside the indication approved by the DCA and listed in the MOHMF

The determination of the scope of use of SAM was derived by critical reviewing of the SAM application process, the indication for SAM and rationale for the SAM application. The classification of the scope of use of SAM is as stated below:

• i.
  Based on the medicine:

  • •
    Life-saving medicine which are not intended to be used to continue the treatment commenced at a non-MOH facility or sample medicines.
  • •
    Medicine with a specific indication whereby no alternative is available in MOHMF.

• ii.
  Based on the patient:

  • •
    The patient have been treated using all available and suitable alternatives in MOHMF but the treatment was ineffective or suboptimal for the patient.
  • •
    The patient developed adverse effect/drug interaction or could not tolerate the treatment using all available and suitable alternatives in MOHMF.

Two researchers reviewed the source documents to determine the classification of the scope of use of SAM. Two other researchers reviewed and validated the classifications. Discrepancies were resolved through discussions and consensus among the researchers. The patients monitoring forms accompanying the repeat SAM applications were further examined for occurrence of side effects and reporting of disease or symptom improvement.

The cost incurred in purchasing SAMs were primarily funded by the MOH. For cost calculation, the unit cost for each medicine was calculated by dividing the pack price by the size to determine cost per tablet or capsule. The cost of any oral liquids was based on the number of bottles needed for the requested duration (up to 12 months). The cost of parenteral medicines was based on the number of ampules or vials required to administer the prescribed dose for the requested duration. The total cost of SAM was calculated by multiplying unit cost with the quantity of medicine required for the requested duration. The unit cost of the medicine was based on the price quotation (lowest quoted price) enclosed with the SAM application form. The quantity of medicine required was extracted from the SAM application form. Manual calculations of quantity of SAM was determined based on the dose, dosing frequency, duration of treatment and shelf-life of medicines (for diluted or reconstituted medicines). The manual calculations of the quantity of SAM was randomly checked by the researchers. Discrepancies were resolved through a consensus discussion between the researchers. The SAM purchased by the patients (out-of-pocket) and borne by other funding sources besides MOH were excluded from cost calculation. Costs were expressed in 2022 Malaysian Ringgit (MYR) and United States Dollar (USD).

2.7. Statistical analysis

Descriptive analysis of per-patient data was conducted using the Statistical Package for the Social Sciences (SPSS) version 24. Continuous variables were summarized using mean (standard deviation) or median (interquartile range) depending on the data normality. Categorical variables were represented using frequencies and percentages.

3. Results

In total, 328 applications corresponding to 74 types of SAMs (Table 1) for 1010 patients with the mean age of 8.7 ± 5.6 years were analyzed (Table 2). As the per-patient data was used for analysis, the denominator for percentage calculation was the total number of patients i.e. 1010. The most common SAM dosage forms were tablet or capsule (n = 556, 55%), injectable (n = 215, 21.3%) and liquid oral formulations (n = 97, 9.6%). The profile of SAM by Anatomical Therapeutic Chemical (ATC) classification system is shown in Table 3. The most common pharmacological group was nervous system (n = 371, 36.7%) followed by antineoplastic and immunomodulating agents (n = 332, 32.9%). The top three SAMs were melatonin (n = 116, 11.5%), scopolamine (n = 77, 7.6%) and cholecalciferol (n = 72, 7.1%).

Table 1.

List of special approval medicines.

Drug name	Strength/concentration	Dosage form
Abacavir	300 mg and 20 mg/ml	Tablet and Oral solution
Blinatumomab	35μg/3 ml	Injection
Cholecalciferol	1000iu and 5000iu	Tablet and Capsule
Cladribine	10 mg/10 ml	Injection
Clofarabine	20 mg/20 ml	Injection
Clostridium Botulinum Toxin Type A	100 IU and 500 IU	Injection
Coenzyme Q10	30 mg	Softgel capsule
Darunavir	600 mg	Tablet
Dasatinib	50 mg	Tablet
Defibrotide	200 mg	Injection
Deflazacort	30 mg	Tablet
Diazoxide	100 mg	Capsule
Dibutyl Squarate Liquid (SADBE)	5 g	Topical liquid⁎
Doxycycline	100 mg	Injection
Dupilumab	300 mg	Pre-filled syringe
Emicizumab	150 mg/ml	Injection
Entecavir	0.5 mg	Tablet
Epinephrine	0.15 mg	Injection
Etoposide	50 mg	Capsule
Everolimus	10 mg	Tablet
Foscarnet	24 mg/ml	Injection
Gabapentin	300 mg	Capsule
Gemcitabine	1000 mg	Injection
Glibenclamide	5 mg	Tablet
Glycopyrronium bromide	1 mg/5 ml	Syrup⁎⁎
Gonadorelin	100μg	Injection
Imatinib	100 mg	Tablet
Interferon Beta 1a	22μg	Injection
Iron (III)-hydroxide Polymaltose Complex	100 mg	Chewable tablet
Lomustine	10 mg, 40 mg	Capsule
Macrogol	10 g	Powder for oral solution
Melatonin	3 mg	Capsule
Melphalan	50 mg/10 ml	Injection
Methadone	5 mg/ml	Syrup⁎⁎
Mexiletine	100 mg	Capsule
Midazolam	10 mg/ml	Buccal Liquid
Mitotane	500 mg	Tablet
Mycophenolate mofetil	250 mg and 1 g/5 ml	Capsule and Oral suspension
Nelarabine	250 mg/50 ml	Injection
Nivolumab	100 mg/10 ml	Injection
Onasemnogene abeparvovec	2 × 1013 vector genomes/ml	Injection
Oxaliplatin	50 mg/10 ml	Injection
Oxcarbazepine	300 mg	Tablet
Oxymetholone	50 mg	Tablet
Paclitaxel	300 mg/50 ml	Injection
Peglyated L-Asparaginase	3750/5 ml	Injection
Perampanel	2 mg and 4 mg	Tablet
Ponatinib	15 mg	Tablet
Protein C concentrate human	500 IU	Injection
Pyrimethamine	25 mg	Tablet
Recombinant Factor VIIa	1 mg	Injection
Risdiplam	60 mg/80 ml	Oral solution
Rufinamide	200 mg	Tablet
Rurioctocog alfa pegol	250 IU	Injection
Scopolamine	1.5 mg	Transdermal patch
Sildenafil	50 mg	Tablet
Sirolimus	1 mg	Tablet
Stiripentol	250 mg	Capsule and Powder for oral suspension
Sulfadiazine	500 mg	Tablet
Sulthiame	200 mg	Tablet
Tacrolimus	0.5 mg and 1 mg	Capsule
Tamoxifen	20 mg	Tablet
Thiotepa	100 mg	Injection
Timolol maleate	0.5%	Eye drop
Topotecan	1 mg and 4 mg	Injection
Triptorelin	11.25 mg	Injection
Valaciclovir	500 mg	Tablet
Valganciclovir	5 g/100 ml	Syrup
Vinblastine	10 mg	Injection
Vindesine	5 mg	Injection
Vinorelbine	50 mg/5 ml	Injection
Zinc + Vitamin C	10 mg + 100 mg/5 ml	Oral solution
Zinc gluconate	50 mg	Tablet
Zonisamide	100 mg	Tablet

^⁎Dibutyl Squarate Liquid (SADBE) 5 g liquid is further diluted to various concentrations, from 2%, 1%, 0.5%, 0.1%, 0.01%, and lastly 0.001% in acetone by in-house non-sterile production unit.

^⁎⁎Prepared by in-house non-sterile production unit.

Table 2.

Profile of patients with SAM applications.

Characteristics	Number of patients (%)
Total (n)	1010
Gender
Male	552 (54.7)
Female	458 (45.3)
Ethnicity
Malay	736 (72.9)
Chinese	163 (16.1)
Indian	82 (8.1)
Others	29 (2.9)
Age
Neonate (birth to 1 month)	20 (2.0)
Infant (>1 month – 1 year)	60 (5.9)
Children (>1–12 years)	641 (63.5)
Adolescent (>12–18 years)	262 (25.9)
Adult (>18 years)	27 (2.7)
Mean age (years ±SD)	8.7 ± 5.6
Mean weight (kg ± SD)	23.87 ± 13.73
Mean body surface area (m2 ± SD)	0.88 ± 0.18
Applicant's department/sub-speciality
Pediatric Neurology	343 (34.0%)
Pediatric Oncology	235 (23.3%)
Pediatric Dermatology	162 (16.0%)
Pediatric Nephrology	96 (9.5%)
Pediatric Gastrology	40 (4.0%)
Pediatric Palliative Care	38 (3.8%)
Pediatric Endocrinology	26 (2.5%)
Ophthalmology	25 (2.4%)
Neonatology	15 (1.5%)
Pediatric Infectious Disease	13 (1.3%)
Pediatric Surgery	4 (0.4%)
Pediatric Cardiology	4 (0.4%)
Otorhinolaryngology	3 (0.3%)
Radiology	3 (0.3%)
Urology	3 (0.3%)

SAM = Special Approval Medicine.

Table 3.

Per-patient data on SAMs based on the WHO ATC classification.

ATC classification Top 3 prescribed medicines⁎	n (%)	Number of SAM applications (%)	Types of SAM applications (new/repeat)	Cost [MYR (USD)]
Nervous system	371 (36.7)	44 (13.4)	26/18	1, 506, 349.32 (359, 940.21)
Melatonin	116 (11.5)
Scopolamine	77 (7.6)
Oxcarbazepine	56 (5.5)
Antineoplastic and immunomodulating agents	332 (32.9)	202 (61.6)	182/20	4, 943, 015.09 (1, 181, 127.03)
Sirolimus	68 (6.7)
Peglyated L-Asparaginase	48 (4.8)
Vindesine	35 (3.5)
Alimentary tract and metabolism	153 (15.1)	18 (5.5)	17/1	80, 622.30 (19, 264.59)
Cholecalciferol	72 (7.1)
Macrogol	39 (3.9)
Zinc + Vitamin C	25 (2.5)
Blood and blood forming organs	47 (4.6)	20 (6.1)	15/5	1, 755, 239.38 (419, 412.17)
Iron (III) hydroxide polymaltose complex	30 (3.0)
Defibrotide	9 (0.9)
Rurioctocog alfa pegol	4 (0.4)
Dermatologicals	33 (3.3)	5 (1.5)	4/1	217, 986.20 (52, 087.52)
Timolol maleate	29 (2.9)
Dupilumab	4 (0.4)
Cardiovascular system	17 (1.7)	5 (1.5)	4/1	12, 312.93 (2, 737.29)
Epinephrine	12 (1.2)
Co-enzyme Q10	4 (0.4)
Mexiletine	1 (0.1)
Antiinfectives for systemic use	17 (1.7)	16 (4.9)	11/5	180, 076.30 (43, 029.00)
Abacavir	5 (0.5)
Valganciclovir	4 (0.4)
Darunavir	2 (0.2)
Musculo-skeletal system	13 (1.3)	9 (2.7)	9/0	20, 515.44 (4, 902.14)
Clostridium Botulinum Toxin Type A	7 (0.7)
Risdiplam	3 (0.3)
Onasemnogene abeparvovec	3 (0.3)
Various	8 (0.8)	4 (1.2)	3/1	6, 227.74 (1, 488.11)
Gonadorelin	5 (0.5)
Diazoxide	3 (0.30)
Genito urinary system and sex hormones	17 (1.7)	3 (0.9)	2/1	22, 645.28 (5, 034.52)
Sildenafil	15 (1.5)
Tamoxifen	2 (0.2)
Antiparasitic products, insecticides and repellents	1 (0.1)	1 (0.3)	1/0	264.60 (63.23)
Pyrimethamine	1 (0.1)
Systemic hormonal preparations, excluding sex hormones and insulins	1 (0.1)	1 (0.3)	1/0	3, 103.80 (741.65)
Deflazacort	1 (0.1)
TOTAL	1010	328	275/53	8, 748, 358.38 (2, 090, 408.87)

ATC = Anatomical Therapeutic Chemical; SAMs = Special Approval Medicines; WHO = World Health Organization.

^⁎Only for groups with >2 medicines per ATC classification.

The SAM used for off-label indications were analyzed for 532 (52.7%) patients. The off-label status per DCA, MOHMF as well as DCA and MOHMF were 16.7%, 6.8% and 4.9%, respectively. The category and scope of SAM is shown in Table 4. Unregistered, non-formulary medicines were applied for 47.3% (n = 478) of the patients while unregistered, formulary medicines were applied for 3.5% (n = 35) of the patients. This resulted in the overall SAM applications for unregistered medicines for 513 patients (50.8%). On the other hand, registered and unregistered non-formulary medicines were applied for 359 (35.5%) and 478 patients (47.3%), respectively. In total, 837 patients (82.9%) were involved in the SAM applications for non-formulary medicines. The majority of the SAMs (64.7%) were applied to substitute the available alternatives in MOHMF which were ineffective or sub-optimal for the patients (Table 4).

Table 4.

Category and scope of use of SAMs.

Category of SAMs	n (%)
Registered, non-formulary medicines	359 (35.5)
Registered, formulary medicines used for indications outside those approved by the DCA or MOHMF	138 (13.7)
Unregistered, formulary medicines	35 (3.5)
Unregistered, non-formulary medicines	478 (47.3)
aScope of SAMs	n (%)
Life-saving medicine which are not intended to be used to continue the treatment commenced at a non-MOH facility or sample medicines	22 (2.2)
Medicine with a specific indication whereby no alternative is available MOHMF	363 (35.9)
The patient have been treated using all available and suitable alternatives in MOHMF but the treatment was not effective or suboptimal for the patient	653 (64.7)
The patient developed adverse effect/drug interaction or could not tolerate the treatment using all available and suitable alternatives in MOHMF	282 (27.9)

DCA = Drug Control Authority; MOH = Ministry of Health; MOHMF = Ministry of Health Medicines Formulary; SAMs = Special Approval Medicines.

^aNumber of patients fulfilled more than one scope of use of SAM = 310.

The proportion of new and repeat SAM applications were 83.8% and 16.2%, respectively. Among the 262 patients with repeat applications, 93.8% reported disease or symptom improvement while 1.9% experienced side effects. The total cost of SAMs was MYR 8,748,358.38 (USD 2,090,418.86) (Table 3).

4. Discussion

This study examined the use and characterized the scope of SAMs in a Malaysian tertiary care children hospital. The findings of the study revealed that drugs acting on the nervous system as well as the antineoplastic and immunomodulating agents were the most commonly used SAMs in the study population. Despite the efforts taken to diversify the treatment of cancer²⁸ and neurological disorders in children,²⁹ approved or licensed treatment options for these diseases remains inadequate.³⁰

Up to 17% of SAMs analyzed in this study were used for off-label indications. This data is almost similar to the proportions of off-label prescriptions due to indication (about 20%) that were reported by studies on off-label use of medicines in pediatric patients in various healthcare setting.³¹ Using SAM for off-label indication calls for heightened patient autonomy and poses additional responsibilities on the prescribers. Although obtaining informed consent from the patient for off-label use is recommended in Malaysia,³² other approaches have been suggested in the literature³³ to help prescribers navigate the medical-legal landscape when engaged with off-label prescribing.

In the current study, 82.9% and 50.8% of the patients were involved in the SAM applications for non-formulary and unregistered medicines, respectively. This is parallel to the national trend in the SAM applications for non-formulary and unregistered medicines of about 83.7% and 40.6%, respectively.²³ A high proportion of SAM applications for non-formulary medicines may signal the need to develop a national pediatric formulary encompassing best available evidence from registration data, investigator-initiated research, clinical experience and consensus.³⁴ Besides developing a new pediatric formulary, extension of an existing pediatric formulary with the addition of country-specific information to address country-specific needs have also shown to be successful.³⁵

About 65% of the SAM applications were submitted to substitute the alternatives in the formulary which were ineffective or sub-optimal for the patients. This finding contradicts data reported by another study conducted in Spain¹⁸ whereby the most common cause of non-formulary prescription was unavailability of a formulary therapeutic alternative. Side effects towards SAM were reported in about 2% of the patients with repeat applications. An analysis of ADR reports till the year 2019 at the same study site showed that about 8% of the ADR reports involved SAMs³⁶. Given the potential for ADR in pediatric patients with SAM, the development of ADR reporting forms suitable for reporting cases related to the use of SAM is warranted.

To the best of our knowledge, this was the first study conducted to examine the use of SAMs at a tertiary care children hospital in Malaysia. The strength of the study lies in the generation of evidence using real world data. This study had signposted that the Malaysian regulatory and formulary boundary could be reengineered to include effective and safe alternatives for children. This study, however, is subject to several limitations. The cost-saving strategies employed at the study site was not taken into account in the drug cost calculation in this study. The occurrence of side effects and reporting of disease or symptom improvement was obtained from the study's source documents and lacks verification against patient's progress notes or adverse drug reaction report.

To obtain valuable clinical relevance, future research should identify the effectiveness and risks of SAM in children using “real-world approach” of effectiveness studies. This could be achieved by conducting Hypothesis Evaluating Treatment Effectiveness (HETE) studies³⁷ involving the SAMs profiled in this study. Firstly, the most commonly used SAM with the highest cost implication need to be identified. Following this, the critical clinical parameters and cutoffs that will define sufficient efficacy and unacceptable safety for the identified SAM should be established. Once the mapping of SAM with its relevant efficacy and safety parameters are established, structured data collection can be implemented as a routine practice to evaluate whether a treatment effect observed under controlled environment gives the same result in the real world. These results may lead to real world evidence-based treatment recommendations that can be implemented to benefit healthcare provision.

5. Conclusion

The SAMs in the tertiary care children hospital in Malaysia involved unregistered, non-formulary medicines used as a substitute for the available alternatives in MOHMF. A concerted effort is warranted in exploring supplementary mechanisms to reconstruct the medicine registration process and formulary system towards facilitating enhanced provision of treatment for pediatric population.

Funding

This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

CRediT authorship contribution statement

Shamala Balan: Conceptualization, Formal analysis, Writing – review & editing, Supervision, Project administration. Koo Kaitian: Methodology, Data curation. Muhamad Danial Muhamad Hamdan: Investigation, Writing – original draft. Lee Su Vin: Investigation, Writing – original draft.

Declaration of Competing Interest

The authors declare no competing interests.