1. Introduction
According to the World Health Organization (WHO), access to medications is a ubiquitous and fundamental right for individuals to achieve good health standards [
1], and shortages of these drugs are a global challenge influencing numerous medicines in diverse therapeutic areas. These shortages have been influencing cancer treatment that is comprised of agents with costly drugs having a low therapeutic index [
2], few alternative options, and agents being used in combination. These distinguishing features have led to severe shortage impacts [
3,
4,
5,
6,
7,
8]. Moreover, most countries import these expensive agents [
4], leading to higher economic costs for patients and institutions, but the ultimate burden is on patients [
7]. The situation is more critical for pediatric cancer patients [
9]. Chemotherapeutic medicines are one of the top five most affected drug classes [
9], commonly short in developed and developing countries and putting an enormous burden on patients and healthcare organizations [
10]. The condition is more severe in developing regions as fewer drugs are available, with a lack of cancer-related data and increased morbidity and mortality [
11].
Pakistan, a South Asian developing country with accelerating cancer cases, is ranked 154th for health system quality [
12]. The private sector attends almost 70.0% of the population [
12]. The country is a big pharmaceutical hub but imports most of its cancer drugs from other countries. With the increasing cancer burden [
13,
14], absence of a national cancer registry/drug shortage reporting system [
15,
16], the compromised role of drug regulatory authorities, outdated drug policies [
17], inadequate treatment facilities [
18], few research studies [
4,
17], and low availability, the shortages of these drugs further make this issue challenging [
17,
19]. A study conducted in a tertiary care hospital also found a severe shortage of anti-cancer drugs [
17].
Addressing anti-cancer medicine shortages in low-income countries is a difficult task. An in-depth estimation is of the utmost need now to ensure optimal patient care and to tackle the expected mortality and morbidity of cancer. There is a lack of evidence-based research studies to analyze and handle this issue in Pakistan, so the study aimed to evaluate, characterize and assess this issue in Pakistan from the perspectives of pharmacists to deliver ideas to facilitate understanding of anti-cancer drug shortages in Pakistan, their unique nature and to encourage further analysis of policies that could reduce shortages. The study explored the current situation, its determinants, and impacts and adopted both mitigation strategies and recommendations.
2. Materials and Methods
2.1. Study Design and Data Collection
We designed a qualitative study to explore significant anti-cancer drug shortages in Pakistan.
A semi-structured interview guide was designed from a deep literature review and study objectives adopted from similar global studies [
16,
20,
21,
22]. Three investigators reviewed the interview guide. Then, a pilot study was conducted by interviewing three participants from different regions of the country. Based on the feedback from the academic review and pilot study, we modified and refined the interview guide. The three interviewees involved in the pilot study were excluded from the final study. The final form of the interview guide was comprised of five sections. Section one contained general information, section two contained general thoughts about anti-cancer medicines shortages, section three contained reasons of anti-cancer medicines shortages, section four contained impacts, and section five contained adopted mitigation strategies (
Supplementary Materials File S1).
We focused on hospital pharmacists, as they faced anti-cancer drug shortages on the front line; involved in problem evaluation, management and knowledge sharing. They commonly deal with logistics and procurement, directly connected with manufacturers, distributors, suppliers and oncologists. In many hospitals, they act as an information source for other health professionals. Moreover, in Pakistan, access to pharmacists is feasible in comparison to other health professionals [
23].
In the sampling process, we first prepared a list of cancer hospitals (general hospitals with oncology departments or specialized from all public/private sectors) throughout the country. Based on the availability of cancer hospitals, we divide the whole country into five regions (Punjab, Sindh, KPK, Islamabad, and Baluchistan). In each region, the number of pharmacists was selected depending on the population of hospital pharmacists/region, and finally, we invited a total of 30 pharmacists through email and/or phone.
All of the interviews were conducted from August to October 2021, face-to-face or online via Zoom, according to participants’ preference. English is the official language in Pakistan and is used throughout the country, so the interviews were conducted in English and audio-recorded.
2.2. Data Analysis
The audio-recorded interviews were transcribed and analyzed using NVivo through inductive thematic analysis. Data familiarization was acquired by studying the transcribed scripts several times. Firstly, two researchers manually coded the data. Relevant words, statements, and utterances reflecting the research objectives were annotated and initial inductive codes were constructed to partition the data into separately coded sections. Codes from the early interviews were utilized to create a coding schema to analyze later interviews. These emerged codes were used to analyze the data in NVivo. Focused coding was carried out after the initial coding. Focused coding involves the exploration of the relationship between initial codes depending on difference, similarity, sequence, frequency, causation, and correspondence. The finalized inductive codes were segmented into meaningful categories. To conceptualize the data, different categories were combined to generate themes and subthemes. Before developing final themes, transcripts, codes, and categories were recursively examined. To strengthen the reliability of the findings, quantification (recording the frequency per each code) and tabulation were used. Each participant’s response was quantified once, and the outcome suggested by the majority of participants was considered a significant finding. Regular group meetings were held by the research team to ensure that everyone had the same understanding and perspective of the developed categories.
2.3. Consent and Ethics Approval
All stakeholders gave their verbal consent to participate in the research. Prior to commencing the interviews, participants were asked to read the study’s purpose and the confidentiality declaration. Respondents also had the option of terminating their participation at any time. The study did not reveal the names of the respondents, and the audio recordings were saved properly.
4. Discussion
In developing countries, the typology of anti-cancer medicine shortages needs to be explored and studied [
24]. The accessible health professionals (hospital pharmacists) admitted the presence of anti-cancer medicine shortages in their hospital but the frequency of shortages varies. The reason is the varied financial stability of institutions. A survey conducted in Saudi Arabia also reported the presence of oncology drug shortages with similar statistics [
23].
Participants declared that shortages have surged and aggravated in recent years in the COVID-19 pandemic leading to increased prices for these expensive agents. A study on the impact of COVID-19 on global drug shortages emphasized a similar aspect [
25]. Studies in the US also highlighted the increase in medicine shortages during the pandemic [
26,
27].
In Pakistan, the most prominent cause of anti-cancer drug shortages is the compromised role of the drug regulatory authorities. This has led to outdated policies for drug registration, import, license renewal, fixed drug price, and profit margin (dollar fluctuations). Hence, suppliers are hesitant to import these essential molecules. The compromised role also leads to issues in the hand of other stakeholders, for example, unfair distribution, stocking (selling short expiry drugs/increased prices), increased contracts than capacity, and purchasing from the gray market (compromised efficacy drugs) by distributors [
28]. According to a study in Ghana, the compromised role of the drug regulatory authority is the main reason for the lack of access and shortages of necessary medicines in LMICs [
29]. A recent study from Pakistan also highlighted regulatory issues as the prominent cause of shortage [
17]. Some causes related to other stakeholders are the presence of a single supplier/drug, lack of resources, lack of communication among stakeholders, and small market size. However, these issues could also be solved by the regulatory authorities. Another study in Pakistan mentioned similar causes for drug shortages [
16]. Many participants stated that communication among stakeholders within the same institution and among different institutions is very important for handling the anti-cancer drug shortages smoothly [
4]. This cooperation leads to an improvement in operational transparency. A study in Saudi Arabia also agreed that a lack of communication aggravated drug shortages [
30].
Another important cause is the inappropriate inventory management for raw material at the manufacturer’s hands and anti-cancer drugs at the wholesalers’/hospitals’ which led to shortages and the reason could be the mismanagement of the procurement department (absence of competent pharmacists) or just-in-time (JIT) inventory due to budget constraints (absence of support from governmental authority) [
24]. A study conducted at the public hospitals of South Africa stated that continuous monitoring and computerized system played an important role in drug shortage management [
31].
The impacts of anti-cancer drugs shortage in Pakistan, a low-income country with the absence of a national cancer registry/drug shortage platform [
17], increasing cancer cases and fewer registered drugs [
17], are underestimated. Most participants highlighted suboptimal treatment and delayed treatment along with increased out-of-pocket costs. Similar results are found in studies from the US, Egypt [
32] and Morocco [
33]. The results are also consistent with another recent study carried out in Pakistan [
32] and the one carried out in the US where 65.0% of the participants mentioned delayed treatment due to shortage [
16,
34]. A survey of the drug shortages’ impact on acute care institutions in the US also stated that shortages led to delayed treatment (adverse drug interactions) and some drug shortages impacts are expected to be not reported fully [
35]. Studies throughout the globe agree that medicines shortages lead to out-of-pocket costs and if the condition is cancer, then this burden will be huge [
36]. In government hospitals, medicines are available at affordable cost, and if these medicines are short, patients have to purchase expensive medicines or medicines from a gray market with compromised quality. Ultimately, patients/caregivers become hopeless and frustrated [
36]. Some participants also reported the need for an established and competent role of the pharmacist to handle this situation. Similar results were seen in a survey in Pakistan [
32].
From the adopted mitigation strategies for anti-cancer drug shortages, it seems that the professionals are handling the situation well. However, in reality, it is an extremely challenging, time-consuming, and severe situation since both proactive and counteractive strategies are affected by outdated regulatory policies. In the case of proactive activities, even after well anticipation, financial constraints limit the procurement capacity, and only a few private setups or well-established NGO-based hospitals could be able to procure up to their need and for procuring more brands, only a few generics/brands are approved. For counteractive strategies, managing within hospitals leads to a change of protocol (rescheduled expensive treatment with or without compromised outcomes) [
28], delayed treatment, and switching to alternatives (expensive second or third-line agents with less efficacy increased chances of medication error), all three would impact the optimum health outcomes to some extent [
27,
33,
37].
Managing within the country would be challenging since few suppliers supply the drugs throughout countries so most probably the short drug in one institution will be short in others too [
17]. Moreover, pharmacists or patients themselves have to purchase drugs from the gray market, where the short drugs are expensive and have compromised efficacy. In this case, the out-of-pocket cost for the patient will increase more due to purchasing expensive drugs [
33]. Furthermore, arranging through import is an expensive and lengthy process that lags the treatment duration of the patients who are already vulnerable to a chronic condition at a specific disease stage [
17].
A prominent role is required from regulators through (a) introduction of updated policies (policies for registration/import/license renewal/fix drug prices/profit margin/generic prescribing system/drug supply chain management including fair distribution/punishment for breaching); (b) providing financial support to stakeholders (register reputable manufacturers for local manufacturing, contracts with more than one suppliers/drug, the increase financial budget of oncology drugs for hospitals); (c) establishing cancer registry and national level drug shortage platform that would also work as a communication platform; (d) implementing research studies to get actual facts. Other stakeholders should play their role (i.e., manufacturers need to produce quality products/APIs and make a committee to deal with APIs shortages). Distributors should prefer fair distribution and control profit margins. Hospitals need to admit patients depending on their capacity and available stock, develop a drug shortage platform within hospitals, and give full play to the role of the pharmacist; tele-pharmacy can also contribute to those hospitals’ lack of competent pharmacists in this aspect of choosing suitable alternative medicines [
38].
The study is the first of its kind in Pakistan to highlight the experience of pharmacists with anti-cancer medicines shortages through interviews and put forward some recommendations along with some highlighted research gaps. There are several limitations. Firstly, only pharmacists were included. In the future, additional research studies could be conducted to investigate the perceptions of other key stakeholders on anti-cancer medicine shortages. Secondly, there is a possible risk of bias and discrepancy in findings allied with using both online zoom meetings and face-to-face interviews. The study was designed for online zoom meetings in the pandemic era but few pharmacists were hesitant to participate online. For both types of participants, all details including the interview guide schema were shared through email, and concerning queries were answered to minimize potential biases.