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Post Marketing Survelliance Methods – European Union
Objective : Post marketing safety surveillance program are to assess and quantify known or suspected drug safety issues, identify and characterize potential new risks and risk factors following product marketing, and to monitor medication use patterns.
Types of PMS:-
Active Surveillance: It is defined within the European Commission Volume 9A to be the ongoing, proactive monitoring of product use and potential adverse events (AEs) “To ascertain more completely the number of adverse events in a given population via a continuous organised process.” One objective of active surveillance is to detect safety issues early in the post-marketing environment that were not identified during development, such as rare events or latent onset.
Passive surveillance : It is primarily includes the analysis of spontaneous adverse event reports. Sources for reports include regulatory systems. Passive surveillance often involves assembling a series of cases to examine specific types of events, such as overdose and product re-challenge. This method of safety surveillance is limited by incomplete reporting information (which can impede determination of causality), potential underreporting of events, and unknown parameters for calculation of incidence (denominator and numerator).
Stimulated reporting : It is achieved through direct encouragement of event reporting through communication with potential reporters, such as via a Dear Healthcare Provider Letter. Stimulated reporting can be limited by the same factors as passive surveillance: underreporting,
Comparative observational studies : It can be analytic, such as case-control studies, or descriptive, including cross-sectional surveys and cohort studies. Observational studies do not recruit participants into a controlled environment, as in a random-controlled trial, but instead observe the outcome of interest (e.g., a specific adverse or other drug event) in a population that already takes the drug compared to a population that does not. These studies are commonly used to identify side effects rather than evaluate treatment effectiveness, and may be used to calculate relative risk, but usually cannot be used to calculate absolute risk.
Data Collection and Analytical Methods: There are many tools and resources available for post-marketing safety surveillance: spontaneous adverse event report databases, large administrative databases (e.g., Medicaid, managed care organizations, insurers), registries, and electronic medical records. In the UK, for example, Prescription Event Monitoring (PEM,) developed in the 1980’s, uses a questionnaire to collect outcomes information from a panel of all physicians who prescribe a new drug. Notably, PEM does not require the clinician to determine whether there is a causal relationship to the product. This reporting also allows for follow-up on events of interest, such as pregnancy or death.
India’s pre-clinical contract research organisations (CROs) like Bioneeds, Advinus Therapeutics, Syngene and Jai Research Foundation are now looking at non-animal tests like the in-vitro analysis and even considering the advanced computer modelling techniques which are far more reliable to deliver human-relevant results in a day, unlike some animal tests that require a few weeks.
With the prohibition of the animal testing by the Union government and the revision of the Drugs and Cosmetics Rules 1945 inserting a new rule after 148-B with 148-C to forbid animal testing for cosmetics, research institutes like the IISc, NCBS and JNCASR point out that globally sophisticated computer models which accurately predict drug reactions, techniques like the 3-dimensional human cell derived skin model, quantitative structure activity relationships (QSARs) help to replace the use of guinea pigs or mice generating accurate allergic response data.
The departments of pharmacology in international universities have preferred the computerised human-patient simulators to indicate the adverse drug reactions. India with its scientific prowess and research capability could easily adopt the same, stated IISc, NCBS and JNCASR.
Bengaluru-based Bioneeds India, an OECD GLP Certified Pre-Clinical CRO, has already adhered to the European Commission’s Scientific Committee on Consumer Safety (SCCS) SCCS/1297/10 issued on 8 December, 2009 which mandates use of validated alternative methods in toxicological testing. These are Local Lymph node assay, NRU Photo toxicity, Bovine Corneal Opacity Study (BCOP), Dermal percutaneous absorption study (rHES), Direct Peptide Reactivity Assay (DPRA) and In vitro dermal irritation study (Epiderm).
“We anticipated this some time back following the EU directives and finally the Indian government has also taken a stand to implement and passing the message to the global regulators that; India is on par with the ‘Be Cruelty-Free Campaign’. Our scientific personnel are armed with the know-how for in-vitro tests and have pioneered in standardizing and implementing the same. In fact, we are one among the premier CROs in the country to comply with global regulatory guidelines of the European Commission’s SCCS which is still in the preliminary stage of implementation in India,” Dr. SN Vinaya Babu, managing director & chief executive officer, Bioneeds India Private Limited, told Pharmabiz.
However, it would have been better if this decision to ban animal studies for cosmetics becomes a global mandate. India, China and South East Asia are seen as hubs by the US and European Union for pre-clinical research. With the revival of the global economy, there would be a number of opportunities for companies in the region. Therefore adherence to SCCS norms are the need of the hour to grab some of the potential business opportunities, said Dr Babu.
Novartis announced that the Committee for Medicinal Products for Human Use (CHMP) has adopted a negative opinion for the use of RLX030 (serelaxin) in the treatment of acute heart failure (AHF) indicating that further evidence is required for a license to be granted in the EU. This follows the company’s request for re-examination after a previous negative opinion was issued in January. Novartis aims to resubmit for approval as soon as additional data is available from the ongoing global trial programme, including the 6,300 patient RELAX-AHF-2 study, one of the largest and most robust programmes undertaken by a company for an AHF drug.
“We are disappointed that patients in Europe will not have access to RLX030 in 2014 but we believe in the value that RLX030 can bring to patients and are committed to extending the current evidence base to confirm this,” said Tim Wright, Global Head of Development, Novartis Pharmaceuticals. “20 million people across the world face poor quality of life and high risk of death from heart failure and it remains our mission to change the course of this disease with our research and development efforts.”
Heart failure is a debilitating and potentially life-threatening condition where the heart cannot pump enough blood around the body. This, in most cases, happens because the heart muscle responsible for the pumping action weakens over time or becomes too stiff. Heart failure is a significant and growing public health concern affecting over 20 million people worldwide and costing the world economy $45 billion annually.
EMA recommends conditional marketing authorisation for Translarna to treat Duchenne muscular dystrophy
The European Medicines Agency’s Committee for Medicinal Products for Human Use (CHMP) has recommended granting a conditional marketing authorisation for Translarna (ataluren), an orphan-designated medicine for the treatment of Duchenne muscular dystrophy caused by nonsense mutations. Translarna is to be used in patients aged five years and older who are able to walk.
Duchenne muscular dystrophy is a genetic disease that gradually causes weakness and loss of muscle function. Patients with the condition lack normal dystrophin, a protein found in muscles. Because this protein helps to protect muscles from injury as muscles contract and relax, in patients with the disease the muscles become damaged and eventually stop working. There are currently no approved therapies available for this life-threatening condition and the current management of the disease is based on prevention and management of complications.
In the European Union (EU), approximately 18,600 people have Duchenne muscular dystrophy. The disease can be caused by a number of genetic abnormalities. Translarna is for use in the subgroup of patients whose disease is due to the presence of certain defects (called nonsense mutations) in the dystrophin gene, which prematurely stop the production of a normal dystrophin protein, leading to a shortened dystrophin protein that does not function properly. Translarna is thought to work in these patients by enabling the protein-making apparatus in cells to skip over the defect, allowing the cells to produce a functional dystrophin protein.
In January 2014, the CHMP originally adopted a negative opinion for Translarna, but at the request of the applicant, the CHMP started a re-examination of its opinion. Following careful consideration of all available evidence, including a re-analysis of the clinical data submitted by the company, the Committee concluded that the data available are sufficient to recommend a conditional marketing authorisation. Under the terms of the authorisation, the company will be required to provide comprehensive data from an ongoing confirmatory study.
Conditional marketing authorisation is an early access mechanism which allows the Agency to recommend marketing authorisation for medicines that address an unmet medical need for patients suffering from life-threatening diseases even if comprehensive clinical data are not yet available.
The applicant for Translarna is PTC Therapeutics Limited. The company is registered as a micro-, small- or medium-sized-enterprise (SME), and as such benefited from support and incentives offered by the Agency’s SME office.
Because Translarna has an orphan designation, the Agency provided free scientific advice to the applicant during the development of the medicine. Orphan designation and the associated incentives, such as free scientific advice or ‘protocol assistance’, are among the Agency’s most important instruments to encourage the development of medicines for patients suffering from rare diseases.
The CHMP opinion on Translarna will now be sent to the European Commission for adoption of a decision on an EU-wide marketing authorisation.
The European Medicines Agency’s Committee for Medicinal Products for Human Use (CHMP) has recommended marketing authorisation for Gazyvaro (obinutuzumab) in combination with the cancer medicine chlorambucil for the treatment of adults with previously untreated chronic lymphocytic leukaemia.
Gazyvaro has an orphan designation. It is to be used in patients with additional medical conditions who cannot be treated with full dose fludarabine-based therapy.
Chronic lymphocytic leukaemia is a rare type of cancer which affects certain white blood cells called B-lymphocytes. It is a long-term debilitating and life-threatening disease as patients can develop severe infections. Chronic lymphocytic leukaemia accounts for approximately 30 per cent of adult leukaemias. In the European Union (EU), more than 62,000 people were diagnosed with leukaemia in 2012 and over 41,000 people died from the disease.
Chronic lymphocytic leukaemia remains an incurable disease. Treatments currently available generally induce remission, however the disease returns in nearly all patients.
Gazyvaro is a monoclonal antibody that targets B-lymphocytes, thereby helping the body’s immune system to kill the cancer cells.
The main study on which Gazyvaro’s recommendation is based is a phase III trial including 781 previously untreated patients with chronic lymphocytic leukaemia and coexisting medical conditions. The study showed that patients treated with Gazyvaro in combination with chlorambucil lived significantly longer without their disease getting worse compared to patients treated with chlorambucil alone (26.7 months versus 11.1 months) or rituximab plus chlorambucil (26.7 months versus 15.2 months). In addition, the risk of disease progression or death was reduced by 86 per cent when Gazyvaro was given with chlorambucil.
The safety profile of Gazyvaro was in accordance with what would be expected for a monoclonal antibody in this class. Infusion-related reactions, neutropenia and infections were among the most common adverse events reported. Some rare but serious adverse events were reported; however, the toxicity profile of Gazyvaro was considered acceptable in view of its benefits.
The applicant for Gazyvaro, Roche, received scientific advice from the CHMP during the development of the medicine. The advice pertained to quality, non-clinical and clinical aspects of the dossier.
The CHMP opinion on Gazyvaro will now be sent to the European Commission for adoption of a decision on an EU-wide marketing authorisation