All the activities involved in detecting, checking and understanding the harmful effects of the drugs and preventing those side effects of medicines are collectively termed pharmacovigilance. So, the primary purpose of pharmacovigilance is to avoid these adverse reactions of pharmacological products for the safety of the patients. In addition, pharmacovigilance considers all the activities of marketing authorization and the aspects of the practical life of pharmacological drugs. By providing the information on time about the safety of a drug or pharmacological product, pharmacovigilance assures the better health of patients and health professionals.
Pharmacological or medicinal products are checked up to an extent before licensing and marketing those products. The efficacy, potency, and safety are checked in the pre-marketing phase through experimental and trial-based studies. Still, this pre-marketing checkpoint does not provide enough information about the adverse effects of drugs because only a small group of people or patients is used in trial practices. The safety level and other details about the efficacy of a medicine can only be calculated if the risks and benefits of a drug are studied in a vast population, in people coming from different ethnic origins. Thus, pharmacovigilance takes a more profound look into medicinal products' adverse and beneficial effects when licensed and used in many people of diverse ethnic origin.
Origin of Pharmacovigilance
Pharmacovigilance first started in 1937 when 107 people died due to the side effects of the elixir Sulfonamide; sulfonamide contained diethyl glycol as a solvent. Then, due to the discovery of Adverse drug reactions (ADR) over time, there has been a tremendous evolution in the field of pharmacovigilance. Many organizations and committees are working now to carry out pharmacovigilance in the USA and Europe. This resolution in pharmacovigilance finally led to a project of the world health organization in 1968; to get an insight into the globally applicable system to discover the adverse drug reactions that have been neglected in the past. Thus, at the end of 2019, a global pharmacovigilance system of WHO established in around 200 countries.
Sources of Drug Safety Assessment of Hemophilia drugs
Like any other drug, drugs for hemophilia are principally approved through four phases. The initial three phases are undertaken in pre-marketing time, and the fourth and final phase is carried out in post-marketing time. Before evaluation in humans, drugs are checked through various in vitro and in vivo test. Animals and laboratories are used to carry out these tests. The main aim of this phase is to check the molecular and cellular effects of a drug along with its efficacy and potency.
Phase 1 and Phase 2
In phase 1, the drug is administrated to a small number of healthy volunteers. This phase gives some idea about the safety and dosage of the drug. In phase 2, the drug is administered to a small number of patients who have hemophilia. This phase provides us with an idea of the given drug's efficacy, pharmacokinetics, and pharmacodynamics.
Finally, in phase 3, studies are carried out on many patients; the number of patients in phase 3 varies according to the prevalence of hemophilia in different world domains. In phase 3, double-blind and single-blind placebo-randomized studies are recommended.
The above-described studies provide us with knowledge of the efficacy and potency of a drug of hemophilia. Still, they do not provide enough data about drug safety; they can not bring out the adverse drug reactions with accuracy. In addition, a minimal number of people are exposed to the drug in pre-marketing phases compared to several people exposed to medication in the post-marketing step. Therefore, as the pre-marketing trial studies are done quickly, they can't provide information about the adverse effects of the drug's chronic use. Furthermore, these pre-marketing studies don’t provide information about the negative impact of medication on people at higher risk of developing side effects. These people include young children, women, older adults, patients who have multiple comorbidities, e.g. chronic lung or liver disease. So, to bring out the complete results of benefits and harmful effects of drugs, there is a severe need for phase 4 studies or the post-marketing pharmacovigilance.
Phase 4 studies implementation of hemophilia drugs in the European Union
In the European Union, the Adverse drug reactions are reported by physicians and sometimes by the patients to the local representative of the Eudravigilance, the Eudravigilance forwards these reports to the pharmaceutical companies, i.e. to MAH, a detailed analysis of the reported ADR is done by PRAC, that in EMA is responsible for the assessment of drugs on the ground.
In the United States
There are two ways of reporting the ADR in the USA; most of the cases of ADR are written by patients and healthcare professionals to MAH voluntarily, MAH further coveys the reports to the FDA. The other way is to submit the information directly to the FDA through the FDA Adverse Event Reporting System, an online database.
Post Marketing surveillance of hemophilia drugs
There has been an evolution in the treatment of hemophilia A and B in recent years. Many new drugs are being used. These drugs include coagulation factors VIII and Factor IX with extended half-life. The PEGylayed, Fc- and albumin fused elements are also being used. In addition, many non-factor medicines that are used subcutaneously include a monoclonal antibody emicizumab and the inhibitors of natural anti-coagulating proteins. The ARDs associated with the hemophilia drugs and the pharmacovigilance moves to cope with those side effects are described below.
Common ADRs of hemophilia Drugs
The most encountered ADR of hemophilia drugs include the allergic reaction and formation of alloantibodies; these alloantibodies inhibit the function of even usual coagulation factors. The previously met adverse effects of infectious transmission during the transmission of plasma or during the administration of hemophilia drugs have reduced to a negligible level in recent years due to the improved methods of sterilization and the screening of blood before transfusion. However, there is still some risk of transferring prions and some viruses that do not have an envelope.
ADRs associated with Administration of Coagulation Factors
The data about immunogenicity against hemophilia drugs is conflicting, but factor VIII of recombinant technology having everyday half-life has nearly double the chances of developing antibodies against it compared with that of plasma extracted factor VIII with average half after first exposure. When the factor Viii with extended half-life efmoroctocog alfa is administered in PUPs, it has antibody development in 31 per cent of patients; the simoctocog has antibody development in 28 per cent of patients on first exposure.
In continuation of the above-described immunogenicity against the extended half-life coagulation factors, one of the pegylated factor VIII, the damoctocog alfa pegol, cause the immunological response due to polyethene glycol and loses its efficacy. EMA has authorized pegylated factor VIII/XI for prevention and treatment of previously treated patients of hemophilia only above the age of 12. However, FDA has approved the use of these factors both for children and adults. The EMA cautionary guidelines can de because these factors have caused vacuolization in macrophages, in the cells of renal tubular cells and choroid plexus epithelial cells of the experimental animals.
ADRs of Emicizumab
A bispecific monoclonal antibody called Emicizumab, if given on interval of weeks, can enhance the coagulation caused by activated factor Viii by antagonizing the factor IXa and factor X. It is approved both by FDA and EMA as a prophylactic agent for bleeding both in children and adults. The HAVEN pivotal studies conducted to explore the ADRs of the emicizumab revealed that I cause the only reaction on the local site of injection. Usually, at the area of injection, erythema and pruritis occur that is resolved spontaneously by themselves.
However, later studies showed that emicizumab and the inhibitors of anticoagulant emicizumab had been shown to cause thrombosis of venous origin and microangiopathic thrombosis. The administration of emicizumab with APCC (Activated prothrombin complex concentrate) also increases the risk of thrombosis of the severe type that can lead to death. Therefore, it is directed to avoid the use of emicizumab with a higher concentration of APCC. The ani-drug antibodies against the emicizumab are rare; only in few cases has there been a waning in its activity of mimicking activated factor VIII. As Hemo Times has indicated many times on our site, emicizumab (Hemlibra) currently has 54 fatalities. When Hemo Times started reporting on this data that was provided quarterly by Genentech, which the manufacturer of emicizumab (Hemlibra), they have now decided to withhold this information from the bleeding disorders community and will no longer update this data.
However, according to pharmacovigilance protocol, it is advised to monitor these adverse drug reactions, especially when its administration does not give Proper results in the initial phases. In addition, there are some cases of idiopathic death after the use of emicizumab. Still, there is no proven link between the action of emicizumab and the end of the patients because Genentech withholds this information from the bleeding disorders community.
ADRs of Fitusiran
Although emicizumab is the only drug of the category of non-replacement drug that has been licensed to treat hemophilia, some non-replacement medicines are also under study. Fitusiran is a small molecule that interferes with the RNA and causes the blockage of antithrombin synthesis in the liver. When it blocks the synthesis of antithrombin, the coagulation activity is balanced despite the deficiency of coagulation factors in hemophilia A and hemophilia B. However, during the phase 2 study of its pre-marketing stage, there have been many thrombosis problems in patients with hemophilia A. As a result, the phase 3 study of this drug has been banned by FDA and EMA. However, the manufacturers have again requested the continuation of the trial studies on adult patients. The protocol that needs to be followed in this trial is to keep the dosage very low and the regular monitoring of the thrombin level of the patients.
ADRs of TFPI
The procoagulant activity of the factor VIII and Factor IX is opposed and neutralized by an anti-coagulant protein called Tissue Factor Pathway inhibitor. An aptamer inhibitor of the tissue factor pathway inhibitor was studied. However, its studies were held back in phase 1 due to severe bleeding in healthy individuals who were research subjects in phase 1. Many other monoclonal antibodies that antagonize the action of tissue factor pathway inhibitor had been made and are being studied. These antibodies include concizumab, marstacimab and BAY-1093884. The therapeutic purpose or goal of all these monoclonal antibodies is to inhibit the action of TFPI, thereby reducing the need for the coagulation factors gained from recombinant technology or plasma sources.
The occurrence of thrombosis followed by BAY-1093884 was severe, so its manufacture has been stopped. The data monitoring committee also blocked the manufacture of the concizumab. Still, its manufacture and trial studies have been continued again after a time. The authorities who control all the pharmacovigilance activities will allow the post-marketing surveillance of these drugs only after they fulfil the criteria of the pre-marketing merits.
ADRs associated with Gene Therapy of Hemophilia
Recent research has shown that gene therapy can work for both hemophilia, i.e. hemophilia A and B. The durability of the transgene in hemophilia A patient is almost four years. In patients with hemophilia B, this durability is nearly 10 ten years. However, in the case of hemophilia A, 20-30 per cent of factor VIII activity is reduced in the initial two years. Many studies of gene therapy for the treatment of hemophilia A and B are in progress. However, many gene therapy programs have been banned due to their lesser safety and efficacy in the pre-marketing stage.
A frequent ADR associated with these gene therapies was an elevation of transaminase; in some cases, a decrease in plasma level of some factors has also been reported. The plasma level of transaminase decreased in most of the patients spontaneously but not in all the cases. Apart from these immediate ADRs of gene therapy, there has been some chronic harmful effects. These chronic ADRs include liver carcinoma, fibrosis of the liver, and some immunogenicity related problems. For example, FDA banned a gene therapy program for hemophilia B in recent years because a patient who was subject of study in phase three was diagnosed with hepatocellular carcinoma later. According to the need of the hour, the FDA recommends a long-term follow up to find out all the chronic ADRs of any gene therapy. EMA also advise long,-term follow up for this purpose. The suggested follow up duration of both the firms is around 15 years. Some other organizations also provided practical ways of evaluating all the benefits and harmful effects of gene therapy in the long term.
Surveillance of Adverse Effects of hemophilia Drugs
As described above, the data collected from different sources have shown many adverse drug effects of antihemophilic drugs occurred before and after the marketing of those drugs. So it is necessary to formulate a system to detect those ADRs as early as possible and as accurately as possible. FDA and EMA have put forward their system of drug surveillance in the post-authorization stage. However, pharmaceutical companies' primary duty, i.e. MAHs, to collect data from the ground and implement effective strategies according to the results gained from the collected data.
Many independent, individual initiatives need to be backed up and supported. Making effective data collection networks, e.g. providing the data forms at the hemophilia centres, will help get the actual data about the frequency and severity of ADRs. However, the stack holders of the companies, their regulating bodies and traders must formulate a system of adequate data set to make sure the correct data approach of data collection and production of results without any biased approach.
Work of Peyvandi and his Colleagues on Pharmacovigilance
Peyvandi and his colleagues presented a minimum dataset; their data set was approved by ISTH scientific and standardization subcommittee. The same dataset has been included in the recommendations of EMA. They have also developed an online portal through which they receive data directly from the healthcare workers. The allergic, thrombotic, malignancies and all other aspects of poet-marketing surveillance are recorded through this portal. The other unexpected ARDs of pegylated, Fc-albumin are recorded either annually or after every six months.
European Hemophilia safety Surveillance
European Hemophilia safety Surveillance is another important system established in 2008 to record hemophilia ADRs and Allied disorders. This organization has provided various reports portraying the data of ADRs like allergic reaction, thrombotic events, neurological problems and many more. Designing the registers for collecting data on specific aspects of drugs at hemophilia care centers is another approach that can be beneficial. This data can be further processed and systemized through electronic software to improve treatment practice. EMA has recommended such registers to get the data from the actual grounds. The last important aspect of post-marketing pharmacovigilance is the encouragement of the active participation of the patients in providing the feedback data; the engagement and empowerment of the patients can be of extreme importance in improving the treatment strategies.
Pharmacovigilance is the set of activities that aims to enhance the safety and efficacy of the drugs. Pharmacovigilance of the hemophilia drugs seeks to get the same goal, but it is more focused on the hemophilia drugs. Pharmacovigilance started in 1937 and continued to grow because of the frequency and severity of ADRs of many licensed drugs. The pharmacovigilance in the pre-marketing stage consists of three phases. More and more about the beneficial and harmful effects of a drug is revealed in each sequential step. Finally, in the post-marketing stage, the data about the ADRs and benefits of the drug is obtained either directly from the patients and healthcare professionals or through the medicinal companies. The FDA and EMA both have developed their networks for pharmacovigilance. In the case of hemophilia, many ADRs of the licensed drugs have been observed. These adverse effects include immunogenicity, allergic reactions and thrombotic events. Some of the hemophilia drugs have been banned due to their severe adverse effects in pre-marketing trials. FDA and EMA are supporting many organizations for checking surveillance of the hemophilia drugs in the post-marketing stage. A detailed description of all these aspects of pharmacovigilance is given above.