ADR in Journals: Are They Translated into Regulatory Frameworks?

INTRODUCTION: An adverse drug reaction case report refers to a scientific publication that is written by a health care professional who suspects a casual relationship between a drug and an adverse drug reaction (ADR). ADR case reports help to identify potential risks associated with the use of drug. Most of the case reports do not mention about reporting the ADR to regulatory authorities. With this objective, the aim of this study was to analyze the number of Adverse Drug Reactions (ADR) published as case reports (PubMed indexed journals) from January 2018 to June 2019, and observe if they are translated in regulatory frameworks like Vigibase, and package inserts.
MATERIALS AND METHODS: 321 ADRs were obtained with the keywords "Adverse Drug Reaction". Out of those, 158 were independently extracted by two investigators, observed and categorized according to classes of the drugs, geographic location, severity, hospitalization, Completeness of ADR, whether reported to the regulatory authority (Vigibase), or listed in the package insert. Literature review articles were excluded.
RESULTS: Out of the 158 ADRs, antibiotics accounted for 12.65%, CNS drugs and monoclonal antibodies11.39%, anticancer drugs 9.49%, CVS drugs 4.43%, anti-viral 3.79%, others 45.56%, respectively. According to geographic region, 26 ADRs published were from USA, Australia 4, Italy 3, India 17, Turkey 9, Singapore and UK 1, China 20, Denmark and Canada 2, Japan 10, France 9, Austria 1, Korea 5, South America 3, Switzerland 2, respectively. Depending upon the severity, causality assessment was done only for 45 ADRs, and not done for 113 ADRs. 41.13% patients (from 65 case reports) were hospitalized. Among the 158 ADRs, 14 ADRs were not found in Vigibase. 32 ADRs were not mentioned in the Drug package inserts. When categorized according to the completeness of case reports, weight accounted for1.89%, lab values and procedure for diagnosis, 96.8%, risk factors, 95.56%, prior exposure, 88.60%, Post ADR status, 60.12%, start-stop medication, route of administration, first dose, last dose, duration of illness accounted for 100%, respectively.
CONCLUSION: Depending upon our observation, we have noticed that there is deficiency in reporting of suspected ADRs to regulatory authorities. Reporting can be included as mandatory criteria for ADR case reports. Also, there is an increased need to aware various healthcare workers for reporting ADR. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.

INTRODUCTION

An Adverse Drug Reaction (ADR) case report refers to a scientific publication related to mostly real-world data. It is compiled by a health care professional when he suspects a casual relationship between a drug and an ADR. Such case reports form an important part of post-marketing safety surveillance of drugs. When properly documented, these reports alert clinicians regarding any unwanted effect of drugs and help them to plan treatment accordingly. They often help identify serious rare ADR, which are often missed during clinical trials [1]. Well-documented published case reports have contributed to promoting public safety and health. And hence, various bodies have come up with guidelines for published ADR case reports [2]. Published case reports differ significantly from spontaneous case reports since they enjoy quality-compliant peer review and an immediate wider visibility among the readership, triggering others to report similar cases, and ultimately leading to prescribing restrictions on or withdrawals of the drug from the market depending on the risk [3].

This study was carried out to analyze the number of Adverse Drug Reactions (ADR) published as case reports (PubMed indexed journals) from January 2018 to June 2019, and observe if they are translated in regulatory frameworks like Vigibase, and package inserts.

MATERIALS AND METHODS

The study was a database oriented one. It was conducted over a duration of one month. It was based on an audit of published ADR case reports and case series listed in journals indexed with PubMed (www.ncbi.nlm.nih.gov/pubmed). The keywords used were “Adverse Drug Reaction”. Only full-length articles and free articles that were published between Jan 2018 to June 2019 were included using the extraction filter. The articles included only case reports and case series on ADR. All literature review articles were excluded.

Data was independently extracted by two investigators, observed and categorized according to demographic details of the patients, classes of the drugs, geographic location, severity, duration of hospital stay and completeness of ADR. They were then cross checked as to whether reported to the regulatory authorities (Vigibase) or listed in the package insert, respectively.

Our study did not require an ethical board approval as it is a database based study on ADR case reports. So it did not require the involvement of study participants. However, permission of institution head was taken to present the data in an international conference. Data have been represented using numbers and percentages wherever necessary.

RESULTS

A total of 321 publications on ADRs were obtained. Out of those, 158 (49.20%) were ADR case reports and case series, and were included in the study. Out of 158 publications on ADRs included, 146 were case reports and 12 were case series.

i. Anatomical Therapeutic Chemical Classification (ATC) of Drugs that were Reported to Cause ADR: ADRs are classified according to the Anatomical Therapeutic Chemical classification (ATC) which are shown in Fig. (); out of the 158 ADRs selected, antibiotics lead to 20 ADRs (12.65%), CNS drugs 18 (11.39%), monoclonal antibodies 18 (11.39%), anti- cancer drugs 15 (9.49%), CVS drugs 7 (4.43%), anti-viral 6 (3.79%), others 72 (45.56%), respectively.

ii. Nationality: According to geographic region, there were 16.45% (26 ADRs) published from USA, China 20, 4 from Australia, Italy 3, India 17, Turkey 9, Singapore 1, UK 1, Denmark 2, Canada 2, Japan 10, France 9, Austria 1, Korea 5, South America 3, Switzerland 2, respectively, as shown in Fig. ().

iii. Causality Assessment: Causality assessment was done for 45 (28.48%) ADRs. Out of them, 43(95.5%) were assessed by Naranjo scale, and 2 (4.4%) by RUCAM score. The analysis was not done for 72.78% ADRs. The results are shown in Fig. ().

iv. Severity of ADR: 41.13% (65 case reports) ADRs were severe and required hospitalization. The results are shown in Fig. ().

v. ADRs not Listed in Vigibase: Among 158 ADRs, 9% were not found in Vigibase. They are listed in Table .

vi. Completeness of ADR: There are 17 required parameters and 13 highly desired parameters as proposed by International Society of Pharmaco Epidemiology (ISPE) & International Society of Pharmacovigilance (ISOP) [2]. Here, we analyzed 13 highly desired parameters. When categorized according to the completeness of case reports, weight accounted for 1.89%, lab values 96.8%, risk factors 95.56%, prior exposure 88.60%, procedure for diagnosis 96.8%, Post ADR status 60.12%, start-s- top medication, route of administration, first dose, last dose, duration of illness all accounted for 100% completeness, respectively. Results are shown in Fig. ().

vii. ADRs Not Listed in the Package Insert: ADRs related to the concerned drugs which have been published but not listed in the package insert were about 20.25% (32 ADRs). They are mentioned in Table [18].

DISCUSSION

ADRs are commonly published in many of the medical and pharmacy journals. These are necessary for drawing new and crucial decisions which govern the patients’ health.

Here, in our study, results showed that most of the ADRs are caused by antibiotics, when classified according to ATC classification. Our findings complement the study done by Geer et al. reporting that majority of the ADRs are found in the anti-infective group. They reported that of the 342 ADRs collected, the 4 major drug classes in causing the most number of ADRs were anti-infective 40.92%, including anti-tubercular drugs 13.15%, steroids 14.03%, anti- coagulants 8.77% and NSAIDs 7.89%, respectively. The study further reported that GI tract and CVS are the most commonly affected systems in the body due to ADR [19].

We observed a higher rate of publications on ADR case reports and case series from the developed countries. Corresponding to our study, we found similar results in the study conducted by Aagaard et al. The objective of the study was to characterize ADRs reported to the WHO-ADR database, Vigibase, and to relate data to national income. They found that approximately 85% of the reports were from high-income countries, primarily the US, UK, France, Germany, Canada and Australia. It could be explained that high-income countries submit the largest number of ADR reports to Vigibase due to well established pharmacovigilance systems [20].

In our study, we have assessed ADRs published in PubMed indexed journals for a period of 18 months. It was observed that casualty analysis was performed only on 45 ADRs. And most of them were subjected to Naranjo algorithm (few have been subjected to RUCAM) for the casualty assessment. A previous study demonstrated a similar phenomenon [21]. The researcher reported that authors of published case-reports rarely subject an ADR to a formal causality assessment. This may be because of lack of awareness of clinicians regarding the overall pharmacovigilance process.

Serious adverse events are any unwanted effects from pharmacotherapy which could result in either death or life-threatening complications that require inpatient hospitalization, cause prolongation of existing hospitalization or result in persistent or significant disability/incapacity, or could cause a congenital anomaly/birth defect, or require an intervention to prevent permanent impairment or damage [22]. In our study, we observed that 41.13% (65 case reports) patients were hospitalized out of 158 case reports. The extent of hospitalization due to ADR in South Ethiopia was discussed by Angamo et al. in a prospective cross-sectional study conducted from May 2015 to August 2016 in Ethiopia. Results from the study showed that the extent of admissions due to hospitalization was 10.3% [23].

The extent of hospitalization was discussed comprehensively by Ognibene et al. in a single- center study published in 2018. In this study, hospitalization due to ADR was found to be more in elderly group, in people aged above 65 years, and one of the major contributors of ADR was polypharmacy which constituted about 56.6% of all the admissions. The study concluded that ADRs occurring in elderly patients are a common cause of hospitalization in the internal medicine departments which calls for the development and incorporation of appropriate strategies for identifying high-risk patients to avoid potentially preventable drug toxicities [24]. In our study, we observed that out of 158 ADR publications, 25(15.82%) were from elderly population. Out of the 25 ADR from elderly population, 17 were hospitalized which constituted 70%.

During our course of investigation, we observed that 14 ADRs were not listed in Vigibase. This could be due to under-reporting. Under-reporting is a problem in all of the spontaneous reporting systems, which can vary between countries. Seemingly not all countries have been a part of the WHO Programme for International Drug Monitoring for the same amount of time, and some are selective about the type of reports they submit. We can take an instance of China which showed an increasing trend of ADR reporting in Traditional Chinese Medicine in recent years. But the proportions of reported ADRs by consumers and pharmaceutical companies for other pharmaceutical products remain low [25].

Mahajan et al. discussed regarding the completeness of adverse drug reaction reports in Western India. The study reported a near 80% score in the overall completeness of the ADR report for the year 2015. Our study attests 100% completeness to the start-stop medication, route of administration, first dose, last dose and duration of illness; post ADR, poor weight reporting was seen in the case reports. Although authors may hesitate to document weight in the case reports because of confidentiality concerns, it is important to note that ISPO guideline does not mandate to include name, address and other details that can reveal patient identity [26]. Out of all ADR case reports, 9% (14) ADR were not found in Vigibase and 20.25% (32) were not included in package inserts. It is thus evident that there is some gap in the reporting of ADRs to regulatory platform by the prescribers and consumers of medications. This may be due to lack of awareness of ADR reporting structure, and seeing it as an extra work without any incentive.

CONCLUSION

Depending upon our observation, we have noticed a gap in reporting of the suspected ADRs to regulatory authorities. Reporting to regulatory authorities should be included as a mandatory criteria for ADR case reports. A multipronged approach is necessary to overcome underreporting, taking into consideration the factors affecting underreporting. At the same time, we need to remember that there should be no added barrier to reporting ADRs in the clinical literature. Good quality reporting increases the potential for signal generation, thereby enabling necessary regulatory actions. Attitudes towards reporting and quality of reporting can be easily addressed by educational and training interventions. There should be a formal process for reviewing case series and case reports. And this is why, recently, pharmacovigilance monitoring centers have started submitting ADRs based on publications. A suggestion is that alongside publishing ADR case reports, the same can be submitted to regulatory database. Many healthcare providers and patients, who do report ADRs do so without funding, while those who work for vigilance databases get paid. That reason has been highlighted in many literatures. However, it is important to remember that medical profession is a noble one where healthcare workers do not always look forward for monitory incentives. ADR reporting can be part of the moral responsibility. But, it will be useful for hospitals to have a pharmacovigilance associate to assist in ADR reporting. Onus can be on the pharmaceutical companies also as based on ADR signals, regulatory steps are taken including changes in package inserts. In this regard, it is important that physicians, patients and other healthcare workers are oriented towards the ADR reporting process. Journals can give pointers to authors motivating the regulatory reporting, and ADR reporting form can be filled up for the necessary submission.

Table 1

ADRs not listed in Vigibase.

S. No.	Drug	ADR
1	Benzalkonium chloride	Contact Allergy [4]
2	Dexamethasone intravitreal implant	CMV Retinitis [5]
3	Escitalopram	Milky discharge from breast, mastalgia [6]
4	Nivolumab	Systemic Vasculitis [7]
5	Ocrelizumab	Psoriaisiform dermatitis [8]
6	Paclitaxel	Hand foot syndrome [9]
7	Polymyxin-B	Hyperpigmentation [10]
8	Romiplostim	Myelofibrosis [11]
9	Sirolimus	Severe small bowel angio edema [12]
10	Sipulecel-T	Erythema annulare centrifugam-type eruption [13]
11	Tacrolimus	Lentigines [14]
12	Trastuzumab	Spider telangiectasias [15]
13	Tocilizumab	Cutaneous sarcoidosis [16]
14	Yellow fever vaccine	Toxic epidermal necrolysis [17]

Table 2

ADRs not listed in package insert [18].

S. No.	Drug	ADR
1	Artesunate	Acute pancreatitis
2	Benzalkonium chloride	Contact allergy
3	Bleomycin	Flagellated dermatitis
4	Dexamethasone	CMV retinitis
5	Escitalopram	Milky discharge
6	Golimumab	Erythemamultiforme
7	Hydralazine	Hepatotoxicity
8	Hydrochlorothiazide	Hearing disorder
9	Ivermectin	Fixed Drug eruption
10	Ipilimumab	Lichenoid like reaction
11	Levetiracetam	DRESS/ Cholecystitis
12	Metformin	Nightmares, abnormal dreams
13	Mirabegron	Serum sickness like reaction
14	Nivolumab	DRESS Syndrome
15	Ocrelizumab	Psoriasiform dermatitis
16	Olanzapine	Pressure ulcers
17	Paclitaxel	Hand- foot syndrome
18	Paracetamol	Nicolau syndrome
19	Pheniramine maleate	Fixed drug eruption
20	Polymyxin B	Hyperpigmentation
21	Prembrolizumab	Bullous pemphigoid
22	Pyridostigmine	AV Block
23	Secukinumab	Lichenoid reaction
24	Sipulecel-T	Erythema annulare centrifugam
25	Sparfloxacin	Nail Pigmentation
26	Sunitinib	Acute pancreatitis
27	Tacrolimus	Lentigines
28	Tigecycline	Delirium
29	Tolvapton	Shock
30	Trastuzumab	Multiple spider telangiectasia
31	Golimumab	Erythemamultiforme
32	Valsartan	Involuntary muscle movement