Biological medicines (BMs), defined as molecules derived from a biological source, do not have Adverse Drug Reactions (ADRs) properly quantified premarketing [1]. Furthermore, unlike small-molecule drugs, translation of preclinical data into clinical data is limited [2]. BMs are more immunogenic than small molecule drugs and have complex manufacturing processes [2], such that changes to a manufacturing process can result in differences between batches, which in some cases affects the benefit-risk balance of the medicines [3]. Another factor that may affect the safety of BMs is storage conditions; these molecules are quite sensitive such that even small changes to storage conditions may result in physical alterations, with consequent changes in their safety profile [4].

Biosimilars, similar to originator biological products in terms of quality, safety and efficacy, are manufactured by different companies using different manufacturing processes from each other and from the originator, which results in some structural differences between manufacturers. Despite this, originator BMs and biosimilars share the same international non-proprietary names (INN) [5]. Due to differences between biologicals produced by different manufacturers, agencies have adopted naming conventions for identification purposes. For example, the European Medicines Agency (EMA) uses INN, brand name, and manufacturer [6], while the Food and Drug Administration (FDA) guidelines require that each originator BM, related biological product, and biosimilar medicine bear a non-proprietary name in combination with a distinguishing suffix consisting of four lowercase letters that lack any meaning [7]. Furthermore, as some manufacturing changes [8] or distribution issues may affect the product’s quality and subsequently its safety [9], robust pharmacovigilance (PV) systems should not only identify which biological medicine or biosimilar is affected but also which batches are affected [7].

The expiry of originator biological medicines patents has allowed developing countries such as Zambia to use more affordable biosimilars, several of which are currently registered with the Zambia Medicines Regulatory Authority (ZAMRA) [10]. As a member of the Southern African Development Community region, Zambia has aimed to harmonise PV of BMs with other countries in the region whilst ensuring they meet World Health Organization (WHO) global standards [4]. Some considerations highlighted by WHO are the mechanisms of traceability in case of adverse events, storage requirements of biologicals, manufacturing variability with consequent differences between batches and manufacturing companies, and immunogenicity [11].

Healthcare professionals (HCPs) must know that changes to the manufacturing process of BMs can result in immune reactions. They must possess the knowledge and understand biosimilar medicines and their PV [12]. This is important because poor knowledge of biological and biosimilar medicines can alter the confidence in the safety and efficacy of these products [13], as well as prescription [12]. Studies conducted elsewhere have revealed that HCPs are unfamiliar with originator biological and biosimilar medicines despite having them in their practice [14] [15] [16].

Healthcare professionals extract information to include in an ADR report from patient medical records (PMRs) [17]. For biological medicines, this means that brand names (or another identifier) and batch numbers must be used during the prescribing, dispensing, and administration, to be included in the ADR report for their PV to be effective. Studies conducted in other countries have shown that ADR reports have been made for these products, but in such a way that the responsible product, its batch number and manufacturer, cannot be traced [5] [15]. If this practice continues, the prescription of harmful originator biotherapeutic products and biosimilar medicines will continue.

Since the licensing of biological medicines in Zambia, there have been no studies to determine the familiarity of HCPs with biological and biosimilar medicines, knowledge of the factors (manufacturing process changes, immunogenicity, and storage) that alter the safety of biologicals, as well as the details required for proper identification of biologicals in reporting adverse events. Some biologicals currently used in Zambia are hospital administered, and some biosimilars are marketed by different marketing authorisation holders [10]. Currently, it is also unknown how these medicines are recorded during prescribing, dispensing, and administering to patients and if brand names or batch numbers are included in ADR reports.

This study investigated the familiarity, knowledge, and practices of HCPs regarding the PV of BMs at University Teaching Hospitals in Lusaka, Zambia.

A total of 245 responses were received following the distribution of 355 questionnaires, giving a total response rate of 69%. Seventy-six questionnaires were distributed to doctors (50 responded, 66%), 199 to nurses (132 responded, 66%) 51 pharmacists (43 responded, 84%), and 29 pharmacy technologists (20 responded, 69%). Ten questionnaires were excluded for analysis because the respondents were non-prescribing doctors, did not indicate their profession, or did not indicate which hospital they practised at.

This study investigated the familiarity, knowledge, and practices of HCPs regarding the PV of BMs at selected hospitals in Lusaka, Zambia. Most HCPs were familiar with BMs (48.9%) but only to the point of having a basic understanding, while most HCPs (40.9%) had never heard of the term “biosimilar medicine”. Despite this, up to 84.7% of HCPs indicated that these medicines were prescribed, dispensed, and administered in their practice. This is similar to other studies conducted in Latin America [15], Malta [14], and Ireland [5], which showed that, despite being unfamiliar with biosimilars, many used them in their practice. HCPs must be educated about BMs that they prescribe, dispense, and administer to their patients as they have additional PV considerations from small molecule drugs.

The current study showed that those who were familiar (i.e., had a basic or complete understanding) of the terms biological medicine and biosimilars had higher mean scores when their knowledge of PV considerations was assessed. Furthermore, many HCPs (74.1%) thought that using non-proprietary names in ADR reports of BMs was better than using the brand name, or did not know which was better to use. The lack of knowledge of the importance of the use of brand names in ADR reports of BMs can also influence their use in practice as the PMR serves as the source of information to include in the ADR report. HCPs were asked how BMs are named in PMRs when prescribing, dispensing, and administering, for which almost half (44.2%) indicated they use non-proprietary names. Currently, Zambia has many biosimilars registered for use [10]. If an ADR occurs, it would be difficult to identify the biosimilar that caused it. PV guidelines or legislation must be made specifically for BMs and biosimilars stating that the use of these drugs should be identified using some identifier (e.g., brand names) to enhance their PV. In Europe, legislation was passed in 2012 encouraging HCPs to use brand names in clinical practice [21].

When HCPs were asked about batch number recording when reporting an ADR, HCPs either did not know or thought it was more important to include them for non-BMs than BMs (63%). This inaccurate perception can potentially influence the practice of recording batch numbers in PMRs, since, just like brand name reporting, PMRs would be the source of information for the ADR report. When HCPs were asked whether batch numbers are generally recorded when dispensing or administering BMs to patients, 57.3% indicated that they are not. If an ADR occurred with the use of a BM, including the batch number in an ADR report would prove difficult, if not impossible for the reporter, if batch numbers are not routinely recorded in PMRs. Studies conducted in Latin America [15], Europe [22], and Australia [23], which aimed to determine the lack of inclusion of batch numbers in ADR reports, found that many prescribers did not have the information available at the time of reporting. A solution to this problem would be the education of HCPs on the importance of batch number inclusion in ADR reports and PMRs [17].

In the current study, when HCPs were asked to rank on a scale of 1 to 7 (with 1 representing easy and 7 representing difficult) the ease of recording batch numbers in PMRs, they gave an overall score of 5.2. This may mean that the lack of use of batch numbers when dispensing or administering BMs may also indicate additional barriers to recording them in clinical practice. HCPs in other countries have expressed difficulty in recording batch numbers, some stating that electronic patient records do not have fields to include batch numbers [24], while others have stated that it is impractical to manually record batch numbers when dispensing and administering medicines [17]. This may also be the case at the selected hospitals where the study was conducted.

Assessment of HCPs’ knowledge of the other PV considerations of BMs generally showed poor knowledge. For example, 60% did not know or thought non-BMs pose a greater risk of immunogenicity than BMs, while almost half (46.8%) thought that different batches of BMs are always identical. These incorrect perceptions hamper the PV of BMs. Therefore, HCPs need to be educated regarding these considerations to enhance the PV of BMs.

Biologics and biosimilars must be transported and stored at highly regulated temperatures [25]. Notably, most HCPs (81.3%) recognised that storing BMs outside their recommended storage conditions may introduce or alter immunogenicity. Temperature fluctuations may increase the formation of protein aggregates and therefore affect the product quality [25].

To check whether HCPs knew under which conditions reporting an ADR was important, 7 questions were asked. Poor knowledge was demonstrated for some questions. For example, almost half (48.5%) did not know or thought that all serious ADRs were known before marketing, and 29.4% thought that one case did not contribute significantly to knowledge of medicinal risk. A study conducted among private healthcare facilities in Lusaka, Zambia also showed that only 42% of HCPs knew that serious ADRs can also be detected after the marketing of drugs [26]. A systematic review of 45 articles found that indifference (perceptions that one case does not contribute much to the knowledge of the risk of medicine) was a reason for the under-reporting of ADRs in 67% of the articles [27].

HCPs’ perception of their knowledge of how to report ADRs was assessed. Less than half (37.9%) of HCPs indicated that they have adequate knowledge on how to report an ADR. This lack of knowledge seems to be a common theme in many PV studies [28] [29], including a study conducted among HCPs at the selected hospitals in Lusaka in 2014. In the study, only 22.2% of the HCPs had prior PV training [20]. One possible solution to tackle this lack of knowledge would be incorporating PV education into undergraduate training programs, as well as incorporation into continuous professional development activities.

Over half (53.6%) of HCPs knew they could report ADRs via hardcopy report forms. However, few knew that they could report ADRs via the Med Safety app (16.6%) and the ZAMRA website (34.9%). HCPs have previously cited the lack of ADR report forms as a reason for not reporting ADRs [30], including a 2014 study conducted at the selected hospitals in Lusaka [20]. As such, HCP education on other reporting methods could enhance ADR reporting.

The study presented some limitations; about 30% of HCPs did not respond to the survey questionnaire and therefore this may result in bias that may affect the generalisation of the results.

Only 61.7% of HCPs were familiar with biological medicines; some understood the basics while others had a complete understanding. However, only 38.8% of HCPs were familiar with biosimilar medicines because they had a basic or complete understanding of them. HCPs generally did not score well when their knowledge regarding the PV considerations of biological medicines was assessed. Some HCPs did not know under what conditions they should report ADRs and some ADR reporting methods. Lastly, the practices of some HCPs at the selected hospitals did not enhance the pharmacovigilance of biological medicines.

Future research could look at the ZAMRA ADR database to determine the reporting of brand names and batch numbers in ADR reports of biological medicines.

Ethical approval was granted by ERES Converge IRB and the National Health Research Ethics Board with reference numbers 2021-Mar-014 and NHRA00017/4/05/2021, respectively.

This work was conducted as a requirement for the awarding of a Master’s degree to Michelo Banda under the Eu2P program. We are therefore grateful for the guidance and support granted by the program instructors.

All authors declare no conflict of interest.

Banda, M., Verhamme, K., Mufwambi, W., Mudenda, S., Chabalenge, B., Matafwali, S.K., Mutati, R.K., Hikaambo, C.N., Kampamba, M. and Prashar, L. (2022) Familiarity, Knowledge and Practices of Healthcare Professionals Regarding the Pharmacovigilance of Biological Medicines in Lusaka, Zambia: A Multi-Facility Cross-Sectional Study. Pharmacology & Pharmacy, 13, 230-251. https://doi.org/10.4236/pp.2022.137019

Throughout the questionnaire, tick only the single checkbox that applies under each question and/or sub-question

1) Are you a

5 Consultant 5 Senior Resident Medical Officer

5 Junior Resident Medical Officer 5 Pharmacist

5 Pharmacy Technologist 5 Nurse

5 Other (please specify)……..

To Be Filled In By Medical Practitioners Only

2) How many years are you registered as a medical practitioner?

5 <5 years 5 5 - 9 years

5 10 - 19 years 5 20 - 29 years

5 >30 years

3) How many years have you been in practice?

5 <5 years 5 5 - 9 years

5 10 - 19 years 5 20 - 29 years

5 >30 years

4) Please indicate the therapeutic area in which you practice?

5 Women and newborn hospital 5 Adult hospital

5 Paediatrics hospital 5 Cancer Diseases Hospital

5) Do you ever prescribe medicines to patients under your care?

5 Yes 5 No

5 Other (please specify)……………………………………………..

To Be Filled In By Pharmacist/ Pharmacy Technologist Only

2) How many years have you been practising as a pharmacist/pharmacy technologist?

5 <5 years 5 5 - 9 years

5 10 - 19 years 5 20 - 29 years

5 >30 years

3) Please indicate the therapeutic area in which you practice?

5 Women and newborn hospital 5 Adult hospital

5 Paediatrics hospital 5 Cancer Diseases hospital

To Be Filled By Nurses Only

2) How many years has it been since you first entered practice?

5 <5 years 5 5 - 9 years

5 10 - 19 years 5 20 - 29 years

5 >30 years

3) Are you a (choose all that apply):

5 Registered General Nurse 5 Registered Public Health Nurse

5 Other (please specify)………………………………………………………

4) Please indicate the therapeutic area in which you practice?

5 Women and newborn hospital 5 Adult hospital

5 Paediatrics hospital 5 Cancer Diseases hospital

Adverse Drug Reaction Reporting

An adverse drug reaction is a response to a medicine which is noxious and unintended. An adverse drug reaction can be reported directly to the Zambia Medicines Regulatory Authority (formerly Pharmaceutical Regulatory Authority) or the manufacturer of the medicine. An adverse drug reaction can be reported using hardcopy report forms, via email, online on the ZAMRA website, and using the Med Safety app.

1) Before this survey, did you know that an adverse drug reaction could be reported directly to the Zambia Medicines Regulatory Authority (ZAMRA)?

5 Yes 5 No

2) Before this survey, did you know that an adverse drug reaction could be reported using:

a) Hardcopy ADR report forms?

5 Yes 5 No

b) The Med Safety app?

5 Yes 5 No

c) The ZAMRA website?

5 Yes 5 No

3) Have you ever reported an adverse drug reaction?

5 No (0 times) 5 Yes (1 time)

5 Yes (2 times) 5 Yes (≥3 times)

Do you think that:

1) Do you have adequate knowledge on how to report an adverse drug reaction?

5 Yes 5 No 5 I don’t know

2) Healthcare professionals should report serious Adverse drug reactions even if uncertain that the medicine caused the event

5 Yes 5 No 5 I don’t know

3) Healthcare professionals should report serious adverse drug reactions even if they do not have all the details of the event (e.g. complete patient history, demographic data)

5 Yes 5 No 5 I don’t know

4) All serious adverse drug reactions are known before medicine is marketed

5 Yes 5 No 5 I don’t know

5) One case reported by a healthcare professional does not contribute much to knowledge on medicine risks

5 Yes 5 No 5 I don’t know

6) Patients can report adverse drug reactions independent of a healthcare professional

5 Yes 5 No 5 I don’t know

7) Healthcare professionals should report adverse drug reactions associated with overdose, misuse or error

5 Yes 5 No 5 I don’t know

Biological Medicines: Familiarity

1) How familiar are you with the term biological medicine?

5 Never heard of the term 5 Heard of the term - can’t define it

5 Familiar - I have got a basic understanding

5 Very familiar - I have got a complete understanding

2) How familiar are you with the term biosimilar medicine?

5 Never heard of the term 5 Heard of the term - can’t define it

5 Familiar - I have got a basic understanding

5 Very familiar - I have got a complete understanding

Biological medicines are produced from biological sources, such as animals, human blood, or the cells of a living organism. Examples of biological medicines include monoclonal antibodies (e.g.infliximab, trastuzumab, bevacizumab), insulins (wosulin, insugen), interferon alfa 2b, erythropoietins (wepox, vintor), vaccines and blood products. A biosimilar is a biological medicine which is highly similar to an original biological medicine.

1) Biosimilars are the same as generic medicines

5 Yes 5 No 5 I don’t know

2) In an adverse drug reaction report, it is better to identify a biological medicine by its non-proprietary name (e.g. insulin) instead of its brand name (e.g. Wosulin)

5 Yes 5 No 5 I don’t know

3) In general, biological medicines pose a greater risk of immunogenicity than non-biological (chemical) medicines

5 Yes 5 No 5 I don’t know

4) Different batches of the same biological medicine are always identical

5 Yes 5 No 5 I don’t know

5) Rare adverse drug reactions resulting from changes to the manufacturing process of a biological medicine can always be predicted

5 Yes 5 No 5 I don’t know

6) It is more important to include batch numbers in adverse drug reaction reports for non-biological medicines than it is for biological medicines

5 Yes 5 No 5 I don’t know

7) Keeping a biological medicine outside its recommended storage conditions may introduce or alter the immunogenicity

5 Yes 5 No 5 I don’t know

8) Adverse drug reactions associated with a patient changing between different brands of biological medicine should be reported

5 Yes 5 No 5 I don’t know

Biological Medicines: Practice

9) Are biological medicines prescribed/dispensed/administered in your practice?

5 Yes 5 No 5 I don’t know

10) Have you ever reported an adverse drug reaction caused by biological medicines?

5 Yes 5 No 5 I don’t know

11) In your practice how are the names of biological medicines that have been prescribed/dispensed/administered to patients generally recorded?

5 Brand name (e.g. Wosulin) 5 Non-proprietary name (e.g. insulin)

5 Both brand name and non-proprietary name

5 I don’t know

5 Varies by medicine (please specify)…………………………………………

12) In your practice are the batch numbers of biological medicines that have been administered/ dispensed to patients generally recorded?

5 Yes 5 No 5 I don’t know

5 Yes, but only for some medicines (please specify)…………………………

Please mark your response to the following questions on each scale ranging from 1 to 7

13) Do you believe that recording the brand names of all biological medicines prescribed/administered/dispensed to patients is:

1 2 3 4 5 6 7

Worthless (1) - Valuable (7) 5 5 5 5 5 5 5

Easy (1) - Difficult (7) 5 5 5 5 5 5 5

Any other comments……………………………………………………………

………………………………………………………………………………………

14) Do you believe that recording batch numbers of ALL biological medicines administered/dispensed to patients are:

1 2 3 4 5 6 7

Worthless (1) - Valuable (7) 5 5 5 5 5 5 5

Easy (1) - Difficult (7) 5 5 5 5 5 5 5

Any other comments……………………………………………..………………