Therapeutic monoclonal antibodies and the need for targeted pharmacovigilance in India

Abstract

A growing number of innovative mAb therapeutics are on the global market, and biosimilar versions have now also been approved, including in India. Although efficacy and safety is demonstrated prior to approval, targeted pharmacovigilance is essential for the identification and assessment of risk for any mAb products. We analyzed the ADR data related to mAbs reported to the NCC-PvPI through the spontaneous reporting system Vigiflow during April 2011 to February 2014 to identify mAbs with the highest number of ADR including fatal/serious ADR. Only 0.72% reports were related to mAbs. Although 15 mAbs are approved in the country, only 6 mAbs were reported through Vigiflow. Rituximab was highly reported, and no fatal/serious ADR related to any mAbs were reported during the study period. Our study shows that PvPI is effective and robust system in the detection and assessment of risks associated with the use of mAbs.

Keywords:

• monoclonal antibody
• NCC-PvPI
• Vigiflow
• spontaneous reporting
• targeted pharmacovigilance

Abbreviations

ADR/E	=	adverse drug reactions/event
ADR	=	adverse drug reactions
AMCs	=	ADR monitoring centers
CDSCO	=	Central Drugs Standard Control Organization
CLL	=	chronic lymphocytic leukemia
DCGI	=	Drug Controller General of India
EMA	=	European Medicines Agency
EU	=	European Union
GEAC	=	Genetic Engineering Appraisal Committee
HBV	=	hepatitis B virus
ICSRs	=	Individual Case Safety Reports
IPC	=	Indian Pharmacopoeia Commission
mAb	=	monoclonal antibody
mAbs	=	monoclonal antibodies
MedDRA	=	Medical Dictionary for Regulatory Activities
MHRA	=	Medicines and Healthcare Products Regulatory Agency
MoEF	=	Ministry of Environment and Forests
MoHFW	=	Ministry of Health and Family Welfare
NCC-PvPI	=	National Coordination Centre-Pharmacovigilance Program of India
NHL	=	non Hodgkin lymphoma
NRA	=	National Regulatory Authority
PML	=	progressive multifocal leukoencephalopathy
PSUR	=	Periodic Safety Updates Report
RCGM	=	Review Committee on Genetic Manipulation
rDNA	=	recombinant DNA
SOC	=	System Organ Class
US	=	Unites States of America
USFDA	=	United States Food and Drug Administration
WHO	=	World Health Organization

Introduction

Biologics are drugs derived from living cells, and have high molecular weight and complexity in their structures compared to small molecule drugs. Biologic medicines include recombinant molecules such as mAbs and fusion proteins, as well as other protein therapeutics.¹ Compared to small molecule drugs, these biologics are highly specific and they have revolutionized the treatment for the patients with solid tumors or hematological cancers, immune-mediated disorders and neurological diseases.

A number of mAb products have been on the market for over 15 years, and patents for some of these products have expired already or will expire soon. Thus, manufacturers are producing similar biologic products, which, as the name implies, are similar but not identical to the original product due to variations that can occur in the manufacturing process. A similar biologic in India is defined as,’ A biological product/ drug produced by genetic engineering techniques and claimed to be “similar” in terms of safety, efficacy and quality to a reference biologic, which has been granted a marketing authorization in India by DCGI on the basis of a complete dossier, and with a history of safe use in India’.²

In India, new biologics and similar biologics undergo stringent regulatory processes to gain marketing approval. The process includes approval from the RCGM,^2,3 which functions in the Department of Biotechnology, Ministry of Science and Technology; the GEAC,^2,3 which functions under the MoHFW; and the CDSCO, which is headed by the DCGI and is the apex regulatory body under MoHFW.² The DCGI is responsible for the approval of new drugs, including biologics, in India.

Approximately 40 biologics and similar biologics have been approved for marketing or import in India by DCGI since 1999, among which 15 were mAbs. ⁴ To ensure the safety of drugs in India, the IPC was given the mandate to act as the NCC for the PvPI starting on April 15, 2011.⁵The aim of this study was to review ADRs associated with therapeutic mAbs reported to NCC-PvPI, with a focus on the severe complications that are associated with the use of therapeutic mAbs and that require critical care.

Results

Data from India reported to Vigiflow from April 15, 2011 to February 28, 2014 were analyzed. Of 58827 ICSRs pertaining to drugs of chemical and biological origin reported to Vigiflow during the study period, 424 (0.72%) ICSRs were related to therapeutic mAbs. The 15 mAbs approved for marketing in India by DCGI are shown in Table 1 . Of these, both innovator and similar biologics of rituximab, trastuzumab and infliximab are approved; however, the infliximab biosimilar product was approved after data collection for this report had concluded. The Vigiflow database with respect to India showed only the reports of 6 therapeutic mAbs: rituximab (71.3%), infliximab (0.9%), bevacizumab (1.5%), cetuximab (1.2%), nimotuzumab (1.9%) and trastuzumab (23.7%) ( Fig. 1 ), including innovator and similar biologic products.

Table 1. Status of biologic and similar biologic mAbs in various countries and their therapeutic indications

Therapeutic mAb	Year of approval					Therapeutic indication
	India^Citation4	US^Citation17	EU^Citation16	Australia^Citation18	Japan^Citation19
Basiliximab	1999	1998	1998	1999	2008	Transplant rejection/ immunosuppressant
Daclizumab	2000	1997	1999	2004	X
Rituximab	2000 2007^#	1997	1998	2010 2011^@	2008	Lymphoma, NHL, CLL, Rheumatoid arthritis
Trastuzumab	2000 2013^#	1998	2000	2010 2012^@	2008	Stomach and breast cancer
Gemtuzumab	2002	2000 2010^w		2000^@	2005	AML
Nimotuzumab	2006	X	X	X	X	Malignant glioma, glioblastoma, pancreatic cancer
Cetuximab	2006	2004	2004	2010	2008	Metastatic colorectal cancer, head and neck cancer
Bevacizumab	2012	2004	2005	2010 2009^@	2007	Non-small cell lung, colorectal, kidney cancer, glioblastoma
Panitumumab	2013	2006*	2007	2008	2010	Metastatic colorectal cancer
Itolizumab	2012	X	X	X	X	Psoriasis
Infliximab	2010 2014^#	1998	1999 2013#	2005^@	2008^@	Crohn's disease, spondylitis, ulcerative colitis, psoriatic arthritis
Canakinumab	2011	2009*	2009	2013^@	2011	Cryopyrin-associated periodic syndromes, systemic juvenile idiopathic arthritis, gouty arthritis, urticaria
Natalizumab	2010	2004; 2005^w 2006^Re	2006	X	X	Multiple sclerosis
Denosumab	2012	2010*	2011	2012^@	X	Osteoporosis, metastasis fractures, giant cell tumor of bone
Abciximab	2013	1994	X	1995	X	Cardiac ischemic complications

^@-Orphan Drug; w-Withdrawn from market; Re-Re-introduced; *-additional safety monitoring; CLL-Chronic lymphocytic leukemia; NHL-Non-Hodgkin's lymphoma; RA-Rheumatoid arthritis; AML- Acute myeloid leukemia; SRE-Skeletal-related events; Re-Reapproved; #-Similar Biologics; X - Not available/no information

Figure 1. Adverse drug reactions of therapeutic mAbs reported to NCC-PvPI through Vigiflow.

ADRs reported as per the SOC of the MedDRA are shown in Table 2 . Data collected from Vigiflow through February 28, 2014 showed 473 ADRs related to rituximab from India, including reports with concomitant drugs with reaction level preferred. When classified by system organ, ADRs over 5% were skin and appendages disorders (17.1%; n = 81), including alopecia (8.8%; n = 42); central and peripheral nervous system disorder (6.5%; n = 31), including peripheral neuropathy (1.8%; n = 9) and fever convulsions (1.4%; n = 7); psychiatric disorders (5.8%; n = 28), including anorexia (4.2%; n = 20); gastro-intestinal disorders (19.6%; n = 93), including constipation (5%; n = 24), nausea (2.7%; n = 13) and vomiting (4.6%; n = 22); white cell and reticuloendothelial system disorders (6.3%; n = 30), including leucopenia (2.3%; n = 11); ‘body as a whole – general’ disorders (25.8%; n = 122), including allergic reaction (2.9%; n = 14), asthenia (2.9%; n = 14), fever (4%; n = 19), and rigors (11.7%; n = 56) were reported.

Table 2. ADR of therapeutic mAbs with respect to primary SOC of MedDRA reported to NCC-PvPI through Vigiflow

SOC disorders	Rituximab (n = 473) (%)	Bevacizumab (n = 10) (%)	Cetuximab (n = 8) (%)	Infliximab (n = 6) (%)	Nimotuzumab (n = 13) (%)	Trastuzumab (n = 153) (%)
Skin and appendages	81 (17.1)	2 (20)	5 (62.5)	3(50)	—	24 (15.7)
Musculo-skeletal system	2 (0.4)	—	—	—	—	4 (2.6)
Central and peripheral nervous system	31 (6.5)	—	—	—	—	9 (5.9)
Vision	1 (0.2)	—	—	—	—	1 (0.6)
Special senses other	22 (4.6)	—	—	—	—	16 (10.5)
Psychiatric	28 (5.9)	—	—	—	2(15.3)	14 (9.2)
Gastro-intestinal system	93 (19.7)	4 (40)	1 (12.5)	1(16.6)	3(23.07)	50 (32.8)
Liver and biliary system	1(0.2)	—	—	—	—	—
Metabolic and nutritional	3(0.6)	1 (10)	—	—	—	1(0.6)
Cardiovascular, general	8 (1.7)	—	—	—	—	1 (0.6)
Heart rate and rhythm	3 (0.6)	—	—	—	—	—
Respiratory system	23 (4.8)	1 (10)	—	1(16.6)	—	2 (1.3)
Red blood cell	11(2.3)	—	—	—	—	5 (3.2)
White cell and reticuloendothelial system	30 (6.3)	1 (10)	—	1(16.6)	1(7.69)	3 (1.9)
Platelet, bleeding and clotting	5 (1.1)	—	—	—	—	—
Urinary system	4 (0.8)	—	—	—	—	1 (0.6)
Body as a whole - general	122 (25.8)	—	1 (12.5)	—	7(53.8)	19 (12.5)
Resistance mechanism	5 (1.1)	—	—	—	—	—
Hearing and vestibular	—	1 (10)	—	—	—	1 (0.6)
Vascular (extracardiac)	—	—	1 (12.5)	—	—	2 (1.3)

The ADR reporting data from India showed that 10 (1.5%) and 153 (23.07%) ADRs were reported for bevacizumab and trastuzumab, respectively. Maximum ADRs reported for both bevacizumab and trastuzumab were related to gastro-intestinal system disorders (40%; n = 4 and 32.6%; n = 50, respectively; Table 2 ), in particular diarrhea. ADR reports on bevacizumab and trastuzumab to NCC-PvPI did not show any fatal/serious events.

Table 3 shows that 99–100% of the reports indicated that the relation to drug was suspected. As 5 of the 6 mAbs are treatments for cancer, some of the ADRs may also be due to concomitant use of chemotherapeutic agents. Out of 473 ADRs reported for rituximab, 98.9% (468) were possible and no report was fatal/serious. Pharmacovigilance data collected from NCC-PvPI during the study period showed that, out of 473 ADRs reported, 1% (n = 5) and 6.7% (n = 32) were specifically reported as related to exposure to innovator and similar biologic rituximab, respectively ( Table 4 ). The remaining 92% (n = 436) were reported only with the international non-proprietary name as rituximab, which thus may include ADRs from either innovator or similar biologic rituximab.

Table 3. Summary of reported ADRs due to the use of therapeutic mAbs by profile and gender

		Relatedness by product [n (%)]				Summary by gender [n(%)]
S.No	Therapeutic mAb	Suspected	Likely	Unknown	Fatal	Male	Female
1	Rituximab (n = 473)	468 (99)	2 (0)	3 (1)	0	263 (55)	210 (44)
2	Bevacizumab (n = 10)	10 (83)	0	0	0	1 (10)	9 (90)
3	Cetuximab (n = 8)	8 (100)	0	0	0	8100)	0
4	Infliximab (n = 6)	6(100)	0	0	0	4 (67)	2 (33)
5	Nimotuzumab (n = 13)	13 (100)	0	0	0	12 (92)	1 (8)
6	Trastuzumab (n = 153)	151 (99.3)	1 (1)	0	0	7 (5)	145 (95)

Table 4. Pharmacovigilance data of rituximab

S.No	SOC disorders	Innovator product (n = 5) [n(%)]	Similar Biologics (n = 32) [n(%)]	Generic name (n = 436) [n(%)]
1	Skin and appendages	2 (33.3)	14 (43.7)	65 (14.9)
2	Musculo-skeletal system	0	1 (3.1)	1 (0.2)
3	Central and peripheral nervous system	0	2 (6.2)	29 (6.6)
4	Vision	0	1(3.1)	0
5	Special senses other	0	1(3.1)	21 (4.8)
6	Psychiatric	0	2 (6.2)	26 (5.9)
7	Gastro-intestinal system	0	3 (9.3)	90 (20.6)
8	Liver and biliary system	0	0	1(0.2)
9	Metabolic and nutritional	0	0	3 (0.6)
10	Cardiovascular, general	0	0	8 (1.8)
11	Heart rate and rhythm	0	0	3 (0.6)
12	Respiratory system	0	1(3.1)	22 (5.0)
13	Red blood cell	0	1(3.1)	10 (2.3)
14	White cell and reticuloendothelial system	0	1(3.1)	29 (6.6)
15	Platelet, bleeding and clotting	0	0	5 (1.1)
16	Urinary system	2 (33.3)	0	2 (0.45)
17	Body as a whole - general	1 (16.6)	5 (15.6)	116 (26.6)
18	Resistance mechanism	0	0	5 (1.1)

Figure 2 shows that the maximum ADR reports (79%) were reported by the generic name of the drug, and only 13.4% reports were classified as innovator products and 7.5% as similar biologics. The data clearly justifies the need for including the brand name of the drug while reporting the ADRs to NCC-PvPI. The ADR reporting form of NCC-PvPI (especially for biologics) needs to be amended to include proprietary name (brand) name, international non-proprietary name, batch/lot number, manufacturer's name, country of origin, lack of efficacy, less effective and over effective,^6,7 so that safety and efficacy difference among the products and manufacturing batch can be monitored and actions can be taken specifically.

Figure 2. Pharmacovigilance data of reference and similar biologics mAb reported to NCC-PvPI.

Discussion

Indian biopharmaceutical companies started establishing a solid foothold in the biologics market in 1997 after the introduction of recombinant hepatitis B vaccine in the Indian market.⁸ Biologics are heterogeneous and may contain aggregated, oxidized, deamidated molecules, as well as various glycoforms, that could affect the safety and efficacy of the product.⁹ Pharmacovigilance of biologics and similar biologics is thus prudent to ensure positive outcomes for patients.

Therapeutic mAbs have been available to Indian patients since 1999, and these products have revolutionized the treatment for various life-threatening disorders. The mAbs provide targeted therapy and are generally considered to be safe, but the risk-benefit can be effectively analyzed only by using an effective post-marketing pharmacovigilance system in the country. ADR data reported to NCC-PvPI until February 2014 were analyzed. During the study period, only 0.72% (n = 424) of ICSRs submitted to PvPI related to therapeutic mAbs, and these were only with respect to 6 mAbs, although 15 mAbs are approved in India. Among 424 ICSRs, ADRs due to rituximab were highly reported. The data were analyzed and summarized in the study for relatedness to product, gender and primary SOC.

The originator and similar rituximab products approved for marketing in India target CD20 on B-lymphocytes and cause depletion of these immune system cells.⁴ Rituximab is therefore used for the treatment of diseases mediated by abnormal functioning of B cells, e.g., hematological cancers, rheumatoid arthritis. The reports for the 6 mAbs that we examined were predominantly about rituximab, but there were no reports on virus reactivation. Various studies have reported ADRs such as listeriosis, reactivation of latent tuberculosis, hepatitis B or C or opportunistic infections^10,11 and PML¹² on treatment with rituximab. The USFDA issued a revision in the label of rituximab to have new ‘Boxed Warning’ information about the risk of reactivation of HBV infection in 2013.¹³ It also notes that viral reactivation of JC virus leads to PML and reactivation of HBV leads to fulminant hepatitis, hepatic failure and death.¹⁴ The UK's MHRA also recommended screening for hepatitis B infection in all patients before starting treatment with rituximab.¹⁵

According to Schedule Y of the Drugs and Cosmetics Act 1940, post-marketing surveillance should be conducted and the PSURs should be submitted to regulatory authority every 6 months initially for a period of 2 y and then annually for another 2 years, serious and unexpected ADRs should be reported within 15 d of its report.²⁰ Post-marketing pharmacovigilance plans should include reporting of ADRs to NCC-PvPI, apart from submission of PSURs to the NRA, which would allow amalgamation of PSUR submission with PvPI.

Similar biologics of rituximab, trastuzumab and infliximab have been approved by DCGI, and these products require stringent pharmacovigilance due to potential differences in quality attributes. As per the Guidelines on Similar biologics, preclinical and clinical data can be reduced by showing comparability with reference products,² but a notice can be issued by the drug regulator for additional safety monitoring to assess the risk-benefit ratio of biologic/similar biologic mAbs in the country.

Our study highlighted that therapeutic mAbs may be under-reported to the national pharmacovigilance system. Because there is limited understanding about the safety of new molecules, particularly in case of similar biologic mAbs, targeted pharmacovigilance is needed. Analysis of individual risk-benefit through targeted spontaneous reporting is highly recommended. Ultimately, this may also help manufacturers to produce safe and effective therapeutic mAbs for patients and help physicians to understand the risks associated with mAbs e.g., in prescribing to patients with histories of latent infections. This study underlines the role of AMCs in identifying local factors that may increase the reporting of ADRs. Instructions issued by the regulator regarding targeted spontaneous reporting and additional transparent safety monitoring are required to ensure the safe and effective use of therapeutic mAbs in the country.

NCC-PvPI and the CDSCO should work together to initiate a culture of reporting of ADR in patients treated with similar biologics, which are under-reported. PSURs on therapeutic mAbs submitted to CDSCO are to be reviewed, and regulatory intervention can be made, or, as with other NRA, drug alerts or warnings may be issued. As NCC-PvPI has already started targeted spontaneous reporting of certain drugs, these biologics and similar biologics also need to be included, so that regulatory intervention on similar biologics based on an Indian database would be more meaningful. NCC-PvPI and CDSCO should sensitize the stakeholders to the fact that intensive monitoring is required to collect ADR/AE on similar biologics, particularly mAbs.

Methodology

The study was a retrospective analysis of ICSRs from India related to therapeutic mAbs reported through spontaneous online reporting system Vigiflow, developed by the Uppsala Monitoring Centre, the World Health Organization's collaborating center for international drug monitoring. ADR/Es reported to NCC-PvPI, IPC, Ghaziabad, India were studied for the period of one year and 9 months, from 15th April 2011 to 28th February 2014. The NCC has been associated with 150 multi-specialty hospitals as AMCs throughout India to monitor the safety of drugs. The data were collected from the reports with/without concomitant drugs and with reaction level preferred. The data were analyzed with respect to the primary SOC as per the MedDRA for age and gender of the patients, the severity of the report and the relatedness of the product using ‘Search and statistics’ tool in Vigiflow.²¹

Disclosure of Potential Conflicts of Interest

No potential conflicts of interest were disclosed.