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The FDA and the EMEA will be sharing information on inspection planning, policy and outcomes and they will be collaboration on inspections.There is an EMEA press release here.
Announcing this pilot Thomas Lönngren, the European Medicines Agency’s Executive Director said: “This important initiative demonstrates the increasing collaboration between the European Medicines Agency and the FDA. It marks an important step to the building of a global regulatory network for supervision of clinical trials. By working together in a collaborative and synergistic manner GCP inspection resources can be used more efficiently.”
The Key Objectives Are:
If you would like more detail in this area please get in touch with Damien Bové damien.bove@idaconsultants.com
Damien Bové works as a drug development consultant (pharmaceutical or biotechnology) and regulatory consultant, we work with our clients to define a drug development target, define a drug development strategy, define a regulatory strategy or define a commercial strategy. Our clients are generally raising funds or looking to license out their technology and we help them achieve it. If you want to know more don’t hesitate to get in touch.
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Posted in clinical, regulatory
Tagged EMEA, FDA, GCP, Good Clinical Practice, Inspection
A full copy is available here. Europe has also been beefing up its regulations in this area, article 1, article 2.
The FDA, are issuing this guidance to provide you, manufacturers of plasma-derived products, with recommendations for performing nucleic acid testing (NAT) for human parvovirus B19 as an in-process test for Source Plasma and recovered plasma used in the further manufacturing of plasma-derived products. Such testing will identify and help to prevent the use of plasma units containing high levels of parvovirus B19. This guidance also recommends how to report to FDA implementation of parvovirus B19 NAT.
Human parvovirus B19 is a small, non-enveloped single stranded DNA virus. Virus clearance studies, using non-human parvoviruses as models for parvovirus B19, have indicated that this virus is highly resistant to all commonly used inactivation methods, including heat and solvent/detergent (S/D) treatment, and is also difficult to remove by filtration because of its small size. More recent studies have demonstrated that human parvovirus B19 may be more readily cleared than certain model animal parvoviruses. The parvovirus B19 can be transmitted by blood components and certain plasma derivatives, and may cause morbidity to susceptible recipients such as pregnant women (and their fetuses exposed in utero), persons with underlying hemolytic disorders, and immune compromised individuals.
We recommend that you implement the following procedures to detect the presence of parvovirus B19 DNA:
If you would like more detail in this area please get in touch with Damien Bové damien.bove@idaconsultants.com
Damien Bové works as a drug development consultant (pharmaceutical or biotechnology) and regulatory consultant, we work with our clients to define a drug development target, define a drug development strategy, define a regulatory strategy or define a commercial strategy. Our clients are generally raising funds or looking to license out their technology and we help them achieve it. If you want to know more don’t hesitate to get in touch.
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Posted in biotechnology, manufacturing, regulatory
Tagged B19, biotech, contamination, FDA, plasma-derived
A full copy is available here.
Both guidelines on the core SmPC for human plasma-derived hepatitis B immunoglobulin, i.e. for intramuscular use (CPMP/BPWG/4222/02) and for intravenous use (CPMP/BPWG/4027/02), have been in operation since November 2006. Other specific guidelines on core SmPC, i.e. Core SmPC for human rabies immunoglobulin for intramuscular use (CPMP/BPWG/3728/02), Core SmPC for human tetanus immunoglobulin for intramuscular use (CPMP/BPWG/3730/02) and Core SPC for human varicella immunoglobulin for intramuscular use (CPMP/BPWG/3726/02) have been in operation since February 2006.
Nevertheless, no guideline on the clinical investigation of these human specific immunoglobulins is currently available.
Due to the recent increase of submission of marketing authorisation applications for human plasma-derived hepatitis B immunoglobulin (HBIG), several questions regarding the required clinical data arise. Furthermore, compliance to the current available Core SmPC being recommended, a specific guidance relating to the clinical investigation of HBIG products appears appropriate. The expansion of this NfG to all specific immunoglobulins needs to be considered.
Considering the similar content of the Core SmPC for human plasma-derived hepatitis B, human rabies, human tetanus and human varicella immunoglobulin, elaborated during a single wave, and the similar pharmacological properties, a single approach can be followed to elaborate the NfG relating to the clinical investigation of specific immunoglobulins. This guideline can address the differences in the clinical requirements of these immunoglobulins and the aspects that could be common for all of them.
Indeed, the clinical approach can be based on three pillars:
Then, some points pertaining to the specific management of the pathology should be addressed. Notably, the following aspects should be studied and taken into account:
The EMEA is looking for industry input into the process of drafting these guidlines and Interested parties with specific interest in this topic will be consulted during the preparation of this guideline including IPFA, PPTA and WHO. Other EMEA Working Parties including Efficacy Working Party and Vaccine Working Party will be involved during the preparation.
If you would like more detail in this area please get in touch with Damien Bové damien.bove@idaconsultants.com
Damien Bové works as a drug development consultant (pharmaceutical or biotechnology) and regulatory consultant, we work with our clients to define a drug development target, define a drug development strategy, define a regulatory strategy or define a commercial strategy. Our clients are generally raising funds or looking to license out their technology and we help them achieve it. If you want to know more don’t hesitate to get in touch.
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A full copy is available here.
This guidance sets out the Medicines and Healthcare products Regulatory Agency’s (MHRA) views on the interpretation of the Medical Devices Regulations.
To obtain information on device related incidents, the Medical Devices Directive requires manufacturers to have procedures in place for systematic review of experience gained from device usage in the post-production phase.
The Medical Devices Directive, through the relevant national regulations [4], requires manufacturers to notify the relevant competent authority (the MHRA in the UK) if:
Some adverse incidents are appropriate for periodic summary reporting:
Some adverse incidents are expected and foreseeable, and as a result may be considered not routinely reportable. These must all be clearly identified in the manufacturer’s labelling, clinically well recognised and quantifiably predictable, well documented in the device master record with an appropriate risk assessment, and clinically acceptable in terms of individual patient benefit.
If you would like more detail in this area please get in touch with Damien Bové damien.bove@idaconsultants.com
Damien Bové works as a drug development consultant (pharmaceutical or biotechnology) and regulatory consultant, we work with our clients to define a drug development target, define a drug development strategy, define a regulatory strategy or define a commercial strategy. Our clients are generally raising funds or looking to license out their technology and we help them achieve it. If you want to know more don’t hesitate to get in touch.
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Posted in devices, regulatory
Tagged medical device, medical devices directive 93/42/EC, vigilance
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a copy is available here.
Drug Regulators Publish ICH consideration on Virus and Vector Shredding Virus / vector shedding should not be confused with biodistribution, e.g., spread within the patient’s body from the site of administration.1 Virus / vector2 includes gene therapy vectors3 and oncolytic viruses.
Assessment of shedding can be utilized to understand the potential risk associated with transmission to third parties and the potential risk to the environment. The scope of this document excludes shedding as it relates to environmental concerns because it is regulated differently in various regions.
The focus of this document is to provide recommendations for designing non-clinical and clinical shedding studies when appropriate. In particular, emphasis will be on the analytical assays used for detection, and considerations for the sampling profiles and schedules in both non-clinical and clinical studies. The interpretation of non-clinical data and its use in designing clinical studies is also within the scope of this paper, as well as the interpretation of clinical data in assessing the need for virus / vector transmission studies.
Information on the known properties of the wild-type strain from which the virus / vector under consideration was derived is essential in guiding the design of shedding studies.
In practice, most viral / vector products currently under investigation are replication incompetent or conditionally replicative. It is likely that virus / vector shedding in these cases would be of a much shorter duration, and, depending on the route of administration, would display a different shedding profile as compared to shedding following infection with the wild-type counterpart.
Other property of the replication-competent virus / vector that should be considered when designing shedding studies would be whether infection is expected to be short- or long-term.
Having suitably qualified analytic assays in place for shedding studies is very important. Assays should be specific, sensitive and reproducible. Quantitative assays are preferred as these will aid in quantifying the probability of transmission. Assessment of interference from the biological sample matrix is important and it might be appropriate to dilute the sample prior to analysis to avoid extensive interference.
Polymerase chain reaction (PCR) and infectivity are the two assays typically used for the detection of shed virus / vector. Use of a quantitative PCR (qPCR)-based assay to detect viral / vector genetic material is recommended.
To accurately assess the potential for transmission of shed material, the use of an infectivity assay is considered important as this will allow for an accurate assessment of the nature of the shed material (e.g., intact virus / vector vs. fragments of virus / vector).
Non-clinical shedding studies help guide the design of clinical shedding studies. The aim of a nonclinical shedding study is to determine the secretion / excretion profile of the virus / vector.
One of the difficulties of investigating virus / vector products in non-clinical studies is the relevance of the animal species as a large number of virus / vector products under clinical evaluation are derived from parental strains which do not readily infect and rarely replicate in non-human species.
Wherever possible the dose and route of administration used in non-clinical shedding studies should reflect those intended for use in the clinical setting.
Known biological properties of the wild-type strain can be used to guide the frequency of sampling after virus / vector administration. In general, one might need to take samples more frequently in the first days following administration in order to detect a transient shedding profile.
The characteristics of the virus / vector, the route of administration, and animal species should be taken into consideration in determining the samples to be collected. Examples of collected samples most commonly include urine and faeces, but could include other sample types such as buccal swabs, nasal swabs, saliva, and bronchial lavage. It is worth considering the samples that should be taken and the volumes that should be collected in order to perform quantitative, suitably qualified analytical assays. For certain secreta or excreta, such as urine, it can be difficult to collect sufficient sample material. Pooling of samples from several animals at the same time point receiving the same dose might be an option so that sufficient sample size or volume can be obtained.
It is important to keep in mind that data from non-clinical shedding studies are useful in guiding the design of clinical shedding studies, particularly as to sample types, sampling frequency, and duration.
The considerations raised above for non-clinical studies are relevant to the design of virus / vector shedding studies in a clinical setting (i.e., route of administration, duration of shedding observed, sample types to be taken and frequency). The known biological properties of the parental virus / vector, the replication competence of the product, dose, route of administration, and patient population will be key factors to consider in the design of clinical shedding studies.
There are a number of factors to take into account when assessing the clinical shedding data and the potential risk associated with transmission from shed virus / vector. An important factor to consider is to identify and characterize what is being shed. Specifically, if the assay used does not distinguish intact from degraded or non-infectious virus / vector, then the data might not be informative as to the potential risk associated with transmission.
Determining how virus / vector is shed is an important factor when assessing the potential risk associated with transmission. One should also consider how much is being shed and the duration of shedding.
In some cases, when shedding is observed, the potential for transmission to third parties might need to be investigated. These investigations would involve evaluation of persons that come into close contact with virus / vector recipients (e.g., family members, healthcare workers) for evidence of transmission. The immunological status of the third party should be considered. A high proportion of the population might already have pre-existing immunity to the virus / vector; in this case, clearance should be effective in those individuals. However, the immune status of the third party contacts could be compromised, e.g., in the elderly or very young, and so clearance mechanisms might be inefficient. Thus the consequences of infection might be more significant in these individuals.
If you would like more detail in this area please get in touch with Damien Bové damien.bove@idaconsultants.com
Damien Bové works as a drug development consultant (pharmaceutical or biotechnology) and regulatory consultant, we work with our clients to define a drug development target, define a drug development strategy, define a regulatory strategy or define a commercial strategy. Our clients are generally raising funds or looking to license out their technology and we help them achieve it. If you want to know more don’t hesitate to get in touch.
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Posted in biotechnology, clinical, pre-clinical, regulatory
This guidance is intended to assist the pharmaceutical industry and other investigators who are conducting new drug development in assessing the potential for a drug to cause severe liver injury (i.e., irreversible liver failure that is fatal or requires liver transplantation). In particular, the guidance addresses how laboratory measurements that signal the potential for such drug-induced liver injury (DILI) can be obtained and evaluated during drug development. This evaluation is important because most drugs that cause severe DILI do so infrequently; typical drug development databases with up to a few thousand subjects exposed to a new drug will not show any cases. Databases may, however, show evidence or signals of a drug’s potential for severe DILI if the clinical and laboratory data are properly evaluated for evidence of lesser injury that may not be severe, but may predict the ability to cause more severe injuries.
DILI has been the most frequent single cause of safety-related drug marketing withdrawals for the past 50 years (e.g., iproniazid), continuing to the present (e.g., ticrynafen, benoxaprofen, bromfenac, troglitazone, nefazodone). Hepatotoxicity discovered after approval for marketing also has limited the use of many drugs, including isoniazid, labetalol, trovafloxacin, tolcapone, and felbamate (Temple 2001). Several drugs have not been approved in the United States because European marketing experience revealed their hepatotoxicity (e.g., ibufenac, perhexiline, alpidem). Finally, some drugs were not approved in the United States because premarketing experience provided evidence of the potential for severe DILI (e.g., dilevalol, tasosartan, ximelagatran).
Only the most overt hepatotoxins can be expected to show cases of severe DILI in the 1,000 to 3,000 subjects typically studied and described in a new drug application (NDA). Overtly hepatotoxic agents (e.g., carbon tetrachloride, chloroform, methylene chloride) are toxic to anyone receiving a large enough dose, and drugs that cause such predictable and dose-related injury generally are discovered and rejected in preclinical testing. More difficult to detect is toxicity that is not predictable or clearly dose-related that occurs at doses well tolerated by most people, but seems to depend on individual susceptibilities that have not as yet been characterized. Most of the drugs withdrawn from the market for hepatotoxicity have caused death or transplantation at frequencies in the range of ≤1 per 10,000, so that a single case of such an event rarely would be found even if several thousand subjects were studied.
In general, the type of liver injury that leads to severe DILI is a predominantly hepatocellular injury. Hepatocellular injury is indicated by rises in AT activities in serum reflecting release of alanine or aspartate aminotransferase (ALT or AST) from injured liver cells. Many drugs that cause transient rises in serum AT activity do not cause progressive or severe DILI, even if drug administration is continued. It is only those drugs that can cause hepatocellular injury extensive enough to reduce the liver’s functional ability to clear bilirubin from the plasma or to synthesize prothrombin and other coagulation factors that cause severe DILI. It is important to identify those drugs as early as possible.
Evidence of hepatocellular injury is thus a necessary, but not sufficient, signal of the potential to cause severe DILI (note, however, that the drugs causing hepatic injury through mitochondrial toxicity may not cause early hepatotoxicity). The frequency of serum AT elevations also is not a good indicator of a potential for severe DILI, because drugs such as tacrine (not a cause of severe DILI) can cause AT elevations in as many as 50 percent of patients. Very high levels of observed ATs may be a somewhat better indicator of potential for severe DILI, but the most specific indicator is evidence of altered liver function accompanying or promptly following evidence of hepatocellular injury.
The single clearest (most specific) predictor found to date of a drug’s potential for severe hepatotoxicity, however, is the occurrence of a small number of cases of hepatocellular injury (aminotransferase elevation) accompanied by increased serum total bilirubin (TBL), not explained by any other cause, such as viral hepatitis or exposure to other hepatotoxins, and without evidence of cholestasis, together with an increased incidence of AT elevations in the overall trial population compared to control.
Hy’s Law is essentially a translation of Zimmerman’s observation that pure hepatocellular injury sufficient to cause hyperbilirubinemia is an ominous indicator of the potential for a drug to cause serious liver injury. Thus, a finding of ALT elevation, usually substantial, seen concurrently with bilirubin >2xULN, identifies a drug likely to cause severe DILI (fatal or requiring transplant) at a rate roughly 1/10 the rate of Hy’s Law cases.
Briefly, Hy’s Law cases have the following three components:
Finding one Hy’s Law case in the clinical trial database is worrisome; finding two is considered highly predictive that the drug has the potential to cause severe DILI when given to a larger population.
The guidance expands upon these key findings in some detail discussing different clinical evaluations etc.
If you would like more detail in this area please get in touch with Damien Bové damien.bove@idaconsultants.com
Damien Bové works as a drug development consultant (pharmaceutical or biotechnology) and regulatory consultant, we work with our clients to define a drug development target, define a drug development strategy, define a regulatory strategy or define a commercial strategy. Our clients are generally raising funds or looking to license out their technology and we help them achieve it. If you want to know more don’t hesitate to get in touch.
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Posted in clinical, regulatory
Tagged clinical development, DILI, Drug, FDA, Liver Injury, Toxicity
Following rapid changes in the area and products making it to the market (related article) The EMEA has published the following “CONCEPT PAPER ON THE NEED TO REVISE THE GUIDELINE ON THE USE OF TRANSGENIC ANIMALS IN THE MANUFACTURE OF BIOLOGICAL MEDICINAL PRODUCTS FOR HUMAN USE (3AB7A OF JULY 1995)”
Recombinant proteins for medicinal use are routinely produced in bacterial or mammalian cell lines. The regulatory requirements to make and test the production lines and cell banks, and the subsequent manufacture and testing of the medicinal product are well established. Many relevant Guidelines are available for production in cell lines. An alternative production platform for recombinant proteins is transgenic animals, where a foreign gene, which codes for a therapeutically useful protein, is inserted into the genome of the chosen
species and is expressed under the close control of a promoter. The recombinant protein is generally expressed in some easily harvested body component such as milk or eggs and does not harm the animal.
A guideline was prepared by CPMP and entered into force in July 1995 (3AB7A). Although it contains advice which was useful for a technology platform which was in its infancy, since it came into force, this production method has progressed significantly and the guidance has not been revised to take account of these advances. The current guideline was prepared at a time when the scientific possibilities for transgenic animals were being investigated and no product had been generated for commercial or clinical trial purposes. In addition, many relevant guidelines, such as the ICH Q5 series had not been prepared.
It is proposed that the scope of the guidance covers the quality issues regarding biological active substances produced by the expression of one or more transgenes stably located in the genome of animals. Production using cloned animals falls outside the scope.
The following improvements to the published guideline have been identified:
The Biologics Working Party recommends developing a guideline on the use of transgenic animals in the manufacture of biological medicinal products for human use to replace the existing guideline.
If you would like more detail in this area please get in touch with Damien Bové damien.bove@idaconsultants.com
Damien Bové works as a drug development consultant (pharmaceutical or biotechnology) and regulatory consultant, we work with our clients to define a drug development target, define a drug development strategy, define a regulatory strategy or define a commercial strategy. Our clients are generally raising funds or looking to license out their technology and we help them achieve it. If you want to know more don’t hesitate to get in touch.
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Posted in biotechnology, formulation, manufacturing
Tagged Biologicals, EMEA, GMP, ICH, ICH Q5, Transgenic animals
EMEA publishes “GUIDELINE ON THE INVESTIGATION OF MEDICINAL PRODUCTS IN THE TERM AND PRETERM NEONATE”. This guideline addresses the considerations and requirements for the design and conduct of clinical trials in premature and term neonates using medicinal products of relevance for the use by this population. It includes background information on the maturation of organs and of body functions.
Neonates are the group of children from birth up to and including the age of 27 days, including term and preterm neonates. They represent a particularly vulnerable subgroup of the paediatric population. Whilst they account for a low percentage of the total use of medicines in childhood, up to 90 % of medicinal products are used unauthorised or off-label in this population, especially if treated on Neonatal Intensive Care Units (NICUs).
There are several reasons as to why few clinical trials of medicinal products have been performed in neonates (e.g. feasibility difficulties linked to: age, small patient group and uniqueness of their diseases.) The Regulation on Medicinal Products for Paediatric Use (Regulation (EC) 1901/2006) creates obligations with regards to conducting clinical trials in paediatric patients including neonates in order to meet the recognised need for authorised medicinal products and the information on the use of medicinal products in children. Therefore clinical trials to investigate medicinal products in the neonatal population have to address the needs of this population (section 9.1).
The guideline aims to provide guidance for the development of medicinal products for use in the neonatal period, defined as from birth up to 27 days post-natal age in term neonates and from birth up to a post-menstrual age of 40 weeks and 27 days in preterm neonates.
Most organ functions are physiologically immature in the neonatal period. The degree of immaturity may be aggravated due to prematurity, intrauterine growth retardation or any potential pathologic condition affecting the neonate. Functional immaturity of physiological processes and organ function predispose neonates to altered pharmacokinetics and pharmacodynamics, leading to potential inefficacy or reduced safety of a medicinal product in the neonate.
Maturational changes are rapid in the post-natal period, and the resulting high variability of the neonates (both inter-individually and intra-individually) has to be considered when investigating medicinal products for use in the neonatal population. Additionally, any medicinal product administered to the neonate may affect the ongoing maturation processes. Major developmental changes should be identified that could significantly influence exposure, safety and efficacy for a given medicinal product. If adequate and possible, not only pharmacokinetic changes due to ongoing maturation but also pharmacodynamic changes as a function of maturation itself should be investigated.
The post-natal cardiopulmonary system adaptation marks the most prominent changes during and after birth. Some of these changes occur instantaneous with the first breath, whereas others occur within hours or days after birth. In general, the impact of lung and heart maturation on PK/PD relationship (e.g., closure of the ductus arteriosus) has to be considered.
Cardiopulmonary monitoring of hospitalised neonates is carried out on a routine basis and these findings should be used and documented for the purpose of a clinical trial as appropriate. Less or non-invasive measures should be used whenever possible (e.g., measurement of blood pressure, heart rate, respiratory excursions and rate; pulse oximetry in at least one site, transcutaneous pO2 and / or pCO2 measuring, electrocardiogram [ECG], echocardiography, and Doppler sonography). Radiologic (e.g. X-ray, MRI) and laboratory (e.g., blood gases, haematocrit) assessments may additionally be required and would need to be synchronised with routine assessments and limited as much as possible.
Critical processes of brain development consist of neuronal proliferation, migration, organisation and myelination. Two main phases can be distinguished with the first occurring between the 8th and 16th week of gestation, consisting of neuronal proliferation and generation of radial glia, and the second phase between 5 months and 1 year of life, consisting of glial multiplication (with neurogenesis and neuroproliferation continuing).
Even if a medicinal product is not primarily developed for an indication related to the CNS, the distribution and penetration into the CNS and the potential effects and neuro-developmental sequelae should be addressed.
Hypoglycemia is an important risk factor for perinatal brain injury. Due to the high metabolic rate and the dependence on glucose as unique source of energy of the brain, any medicinal product affecting glucose metabolism in the neonate may have an effect on the developing brain. This should be carefully taken into consideration when planning a neonatal study.
Measures to monitor brain function include EEG (electroencephalography), amplitude-integrated EEG (aEEG), ultrasonography, Doppler sonography, auditory and visual evoked potential measurements (AEP, VEP), cerebrospinal fluid (CSF) sampling, near-infrared spectroscopy (NIRS), (functional) magnetic resonance imaging (MRI) and positron emission tomography (PET). These measures have different utility, e.g. NIRS allows to continuously assess brain perfusion and oxygen consumption in neonates.
Renal clearance mechanisms include glomerular filtration (GFR), tubular secretion and reabsorption. Glomerular filtration matures faster than the tubular function, and both depend not only on age and maturational status but also on adverse factors occurring in the pre- and post-natal period, including for example intrauterine growth retardation or administration of nephrotoxic drugs to the mother and the neonate.
Serum creatinine is elevated in the first days of life and reflects maternal creatinine and low GFR in the neonate. In premature neonates, the persistence of an elevated serum creatinine during the first weeks of life is the result of a transitory process of tubular creatinine reabsorption. Therefore, to monitor renal function serum creatinine is used after the first week of life in term neonates and after 4 weeks in premature neonates. Before these times, intra-individual changes (related to post-menstrual age) in serum creatinine are used as a guide to renal function.
Hepatic blood flow, plasma protein binding and intrinsic clearance determining hepatic clearance undergo significant post-natal changes. Most enzymatic microsomal systems responsible for drug metabolism are present at birth and their activities increase with advancing post-natal and gestational age. Rapid maturational changes occur during the first weeks of life. Hepatic clearance may be influenced by premature birth, pathologic conditions of the neonate or administration of drugs to the mother or to the neonate.
To predict the exact nature of these consequences requires an understanding of post-natal maturation and main involved enzymes. The ontogeny of specific enzymes is partly described in the scientific literature and may allow estimations of drug metabolism in the neonate. These data should be considered when planning neonatal studies.
If the medicinal product investigated is likely to be eliminated mainly through hepatic metabolism, markers of reduced/normal hepatic function could be included as covariates in the pharmacokinetic data analysis (e.g., in population PK analysis) as well as included in the safety assessment. Monitoring could include standard laboratory and imaging procedures.
Data concerning maturational changes of the neonatal gastrointestinal tract that may influence bioavailability are still limited.
Lymphoid stem cells develop from precursors and differentiate into T, B or NK cells, as well as Antigen presenting cells (APCs) depending on the organs or tissues to which the stem cells traffic. Indeed, both the initial organogenesis and the continued immune system cell differentiation occur as a consequence of the interaction of a vast array of lymphocytic and microenviromental cell surface molecules and proteins secreted by the involved cells. De novo T-cell generation requires a functional thymus. The current paradigm is that the human T-cell repertoire is established during late foetal development and that, by the time of birth, thymectomy does not cause immediate immune deficiency. Thymic epithelial cells – the component of the thymus relevant for T-cell production and selection – involute rapidly after birth. Compared with adult T cells, neonatal T cells secrete increased levels of interleukin-10 (IL-10) following stimulation, but reduced levels of many other cytokines, including IL-2, IL-4, IL-8, interferon gamma (IFN-gamma), transforming growth factor beta (TGF-beta) and tumor-necrosis factor alfa (TNF-alfa).
Antibody response can readily be detected upon challenge in neonates provided to take into account the presence of interfering maternal antibodies. Modern multiparameter cytofluorimetric technology can be employed to assess not only the number of immune cells but also some immune functions such as cytokine production or cytolytic activity. However an effort to develop microassays has to be done to truly assess the different pattern of immune responses in the neonate and in infants in the first years of life. Molecular techniques such as spectratyping for T and B cell repertoire assessment can also be of value.
Changes in body composition during the neonatal period are important factors for altered pharmacodynamic and pharmacokinetic characteristics. Body composition correlates with both gestational and post-natal age, and it continues to change significantly during the first years of life. Age related changes in fat, muscle and total body water composition may produce significant quantitative changes in pharmacokinetic parameters such as volume of distribution. For instance, total body water is highest in the newborn and decreases substantially in the first 4 months of life therefore high water soluble drugs will present a larger Volume of Distribution in the neonatal period potentially requiring larger doses than older children in order to achieve the same desired therapeutic plasma concentrations. On the contrary, the amount of body fat is low at birth and increases progressively in the first months of life. Iatrogenic interventions in neonates could also significantly shift body composition characteristics.
Neonates frequently suffer from conditions that are specific for this subset of the paediatric population, for example respiratory distress syndrome (RDS) or patent ductus arteriosus (PDA). In addition, neonates hospitalised on NICUs often suffer from multiple concomitant conditions, requiring administration of a combination of medicinal products resulting in a high risk of drug interactions. Additionally, adverse reactions in neonates, especially in preterms may trigger specific complications, as for example in relation to susceptibility to necrotising enterocolitis (NEC) or retinopathy of prematurity (ROP). As a further complicating factor, in utero growth retardation may affect pharmacokinetics and pharmacodynamics of drugs at birth and therefore may change the safety and efficacy profile of drugs used in the neonatal period.
The timing of studying a medicinal product in the neonate will depend on the seriousness and uniqueness of the condition to be treated as well as on the availability of alternative treatment options, the potential benefit of a new product, and the target population. Sponsors should refer to ICH Guideline E11.
If possible, clinical data should always be obtained in the least vulnerable population. Depending on the condition, the new product, the target population and further factors according to section 2.1 of the ICH Guideline E11, initial tolerability, PK and safety data should be collected in adults before initiating studies in the neonatal population.
If older children are affected by the same disease or another disease for which the medicinal product may be of use, in general older (less vulnerable) paediatric age groups should be studied before studying the product in the neonatal population.
For conditions exclusively found in neonates, the development should primarily be made in neonates. However, also in such condition, the first studies in man should, if possible, be done in healthy adult volunteers. Sponsors should refer to the ICH Guideline E11.
In order to predict the in vivo situation as much as possible (i.e., as regards efficacy, pharmacokinetics, safety), in vitro studies on human biomaterial, (e.g., on human non-terminally differentiated cells or, if relevant, foetal or neonatal cell cultures) may provide relevant additional information. Examples include enzyme activity, receptor expression and mediator modulation.
The conventional nonclinical studies should be performed including pharmacokinetic, primary pharmacodynamic, safety pharmacology, single- and repeated dose toxicity, genotoxicity, reproductive and developmental toxicity, including peri-/post-natal toxicity testing (e.g., transplacental exposure) and local tolerance studies.
In addition to these conventional non-clinical studies, juvenile animal data should be provided if needed. Juvenile toxicity studies will be necessary if available human safety data and previous animal studies are considered insufficient for a safety evaluation in the intended paediatric age group. If such studies are considered to be not relevant or not feasible, a scientifically data based justification should be provided.
The choice of formulation and route of administration depend on the condition to be treated and the clinical state of the neonate. Age-appropriate formulations and strengths using appropriate excipients must be developed to avoid extemporaneous preparations, even more so for neonates. Novel formulations should be evaluated through preclinical studies and in adults or older children as appropriate before consideration for administration to neonates.
The intravenous route will normally be used in clinically unstable term and preterm neonates. Neonates have a fragile vasculature system, and it may be very difficult to obtain appropriate peripheral or central access. Most common IV routes are peripheral veins (limbs, feet, hands or scalp), umbilical vein, or “long” peripheral lines that can be considered central, whereas internal jugular vein or femoral vein access is uncommon. Neonates may only have a small number of IV lines to administer all medicines as well as blood products, total parenteral nutrition (TPN) and fluid maintenance.
Oral administration should be used when possible and appropriate in the neonatal population, but there is still lack of data on absorption and safety. The way of enteral feeding (e.g., feeding tube, sucking), the time intervals (e.g. continuous, hourly feeds) and amounts of feeding have to be considered and specified.
Rectal administration is not commonly used in this age group, and it is associated with erratic absorption. If considered it must be fully evaluated for safety and efficacy in addition to the appropriate bioavailability studies.
Topical administration may be necessary or suitable for local or systemic effect. Account must be taken of skin immaturity, especially in preterm neonates, and the large and more permeable and moisturised surface area to weight ratio which all predispose to an increased systemic absorption that could lead to toxicity.
Intramuscular administration is not usually a route of choice for neonates because absorption may be slow and unpredictable, varying with postnatal age and clinical state; injections may be painful and cause tissue damage. If the intramuscular route is considered its use must be justified.
Other routes of administration may be required or may be suitable (e.g., endotracheal, inhalation etc). Their use should be justified.
In general, most drugs are developed for adults and older children before they are developed for the neonatal population. All relevant pre-clinical and clinical data in adults and children, or in adults and juvenile animals, should be taken into consideration to find a safe starting dose in neonates. PK / PD modelling techniques, using age appropriate and validated biomarkers, need to be considered to find the optimal dose. For a new medicinal product, the optimal dose has to be clinically verified. Existing physiologically based pharmacokinetic models to predict pharmacokinetic characteristics in the neonatal population may be considered if appropriate.
Pharmacokinetic information is important to support adequate dosing in subpopulations of the clinically studied population and to assess the potential for clinical relevance of toxicity findings in the preclinical studies. However, pharmacokinetics alone is of limited value for extrapolating efficacy and safety from other patient groups, and extrapolation of efficacy will in general need pharmacodynamic data and PK/PD monitoring.
A population PK approach is preferable due to the importance of finding covariates related to dose-individualisation between individuals and over time in the maturating individual. The analysis can be made on rich and/or sparse data depending on the number of patients available and the possibility of developing highly sensitive analytical methods where very small sample volumes could be used.
As for all clinical trials all measures to avoid bias should be included in trials performed in neonates. Therefore uncontrolled trials should be avoided in principle for demonstration of efficacy. They have limited usefulness for the demonstration of safety. On the other hand for randomised trials, in particular those using a placebo, there should be equipoise (genuine uncertainty) at the beginning of the trial and no participants should receive care known to be inferior to existing treatments.
The size of a trial conducted in neonates should be as small as possible to demonstrate the appropriate efficacy with sufficient statistical power. Adaptive, sequential, Bayesian or other designs may be used to minimise the size of the clinical trial. However, a balance between the need to stop recruitment early and the need to obtain reliable safety information should be aimed at.
In addition, clinical trials in neonates should be carried out in experienced neonatology centres with relevant expertise and with appropriate resources, in order to ensure optimum professional conditions for the protection and medical support of the neonates.
Taking into account age classes is of particular importance when recruiting patients within the clinically relevant age interval to optimise the evidence the potential influence of maturation. However, during data analysis, the use of age as a continuous co-variable is recommended whenever possible for the same reason.
The following subgroups within the neonatal population should be recognised as distinct, and the use or not-use of these criteria for stratification should be justified accordingly.
For use in clinical trials in neonates, there is a need to elaborate clinically relevant primary endpoints, linked to the conditions and prospects specific to preterm and term neonates. In addition, the need for establishing age appropriate surrogate endpoints should be considered.
The relationship between phenotype and genotype may be completely different in the neonate as compared to other patient groups. Genetic testing like other tests is subject to prior informed consent. If target genes of interest can be identified, pharmacogenetic analyses of these genes are encouraged. If there are important pharmacogenetic differences affecting pharmacokinetics, efficacy and safety of the medicinal product in the adult populations, pharmacogenetic analysis of the target genes is recommended in neonates. In such cases, the time-dependency (maturation) of the relationship between genotype and phenotype may need to be described.
Within days in the life of preterm and term neonates, there may be large physiological and / or pathological changes in body weight, BSA, and body composition, as indicated above. For example, physiological post-natal weight loss may be more than 10 % of birth weight, and body weight in preterm neonates may increase rapidly, up to threefold during post-natal medical care.
Consequently, there is a need to continuously re-calculate and adjust dosages of investigational medicinal products on the basis of actual weight (or other relevant covariates) or on the basis of results from therapeutic drug monitoring, because fixed or perpetuated dosages are most probably inadequate in terms of efficacy and safety.
Use of placebo in neonates is more restricted than in adults and older children, as neonates are even more vulnerable. Placebo can be used on top of best standard of care, as placebo use does not imply the absence of treatment. The use of placebo may be needed for scientific reasons, for example to quantify variability and to determine treatment effects. Placebo may be warranted in children as in adults when evidence is lacking. As the level of evidence in favour of an effective treatment increases, the ethical justification for placebo use decreases. In all cases, placebo use should be accompanied by measures to minimise its use and to avoid irreversible harm, especially in serious or rapidly evolving diseases.
Preterm and term neonates have very limited blood volume, are often anaemic due to age and frequent sampling related to pathological conditions. The fact that they receive blood transfusions (or iron or erythropoietin supplementation) must not be used as a convenience for increased volume or frequency for blood sampling. The number of samples and/or sample volume should be kept to a minimum.
As in any clinical trial, the study analysis should be carefully planned in advance, taking into account the limited amount of data that may be available with this patient population. The Guideline on Clinical Trials in Small Populations (CHMP/EWP/83561/2005) is fully applicable to studies with term and preterm neonates, and it therefore needs to be taken into consideration for the planning of the study and of the analysis.
As most investigations and procedures carry the risk of pain for the neonates, pain should be prevented, and if unavoidable evaluated, monitored and treated appropriately. Evaluating and monitoring the level of pain may be difficult in the neonate, as scales are based on physiological parameters that can be affected by concomitant diseases and procedures. However, the development and / or use of validated scales is recommended, for example, the Premature Infant Pain Profile (PIPP) or the Neonatal Infant Pain Scale (NIPS) scale for the assessment of pain.
As a general recommendation for hospitalised neonates in a trial, vital signs should be monitored continuously, and related events should be registered according to neonatal definitions (apnea-bradycardia; sustained bradycardia, tachycardia, desaturation, hypotension; fever, hypothermia etc.). Specific age and/or gestation appropriate (e.g., laboratory) reference values and ranges should be used.
The challenging task of pharmacovigilance and follow-up in terms of duration and type depends on the product itself, the target organs, the duration of exposure and other risk factors for sequelae. The potential for adverse drug reactions occurring later in life should be monitored as neonates may have been exposed to medicinal products at a sensitive period in terms of organ maturation. Only a small number of neonates is likely to be included in rather short term trials, thus long-term adverse reactions may not be detected and would require additional appropriate pharmacovigilance approaches and particularly pharmacoepidemiological studies.
If you would like more detail in this area please get in touch with Damien Bové damien.bove@idaconsultants.com
Damien Bové works as a drug development consultant (pharmaceutical or biotechnology) and regulatory consultant, we work with our clients to define a drug development target, define a drug development strategy, define a regulatory strategy or define a commercial strategy. Our clients are generally raising funds or looking to license out their technology and we help them achieve it. If you want to know more don’t hesitate to get in touch.
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Posted in clinical, regulatory
Tagged adverse effects, Clinical Trials, EMEA, ethics, ICH E11, immaturity, maturation, Neonate
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FDA publishes guidance “Use of Serological Tests to Reduce the Risk of Transmission of Trypanosoma cruzi Infection in Whole Blood and Blood Components for Transfusion and Human Cells, Tissues, and Cellular and Tissue-Based Products (HCT/Ps)”
The FDA, are notifying establishments that manufacture Whole Blood and blood components intended for use in transfusion, and establishments that make eligibility determinations for donors of HCT/Ps, about FDA approval of a Biologics License Application (BLA) for an enzyme-linked immunosorbent assay (ELISA) test system for the detection of antibodies to Trypanosoma cruzi (T. cruzi). This test is intended for use as a donor screening test to reduce the risk of transmission of T. cruzi infection by detecting antibodies to T. cruzi in plasma and serum samples from individual human donors, including donors of Whole Blood and blood components intended for use in transfusion, and HCT/P donors (living and cadaveric (non-heart beating)). This guidance document does not apply to the collection of Source Plasma.
The recommendations made in this guidance with respect to HCT/Ps are in addition to recommendations made in the document entitled “Guidance for Industry: Eligibility Determination for Donors of Human Cells, Tissues, and Cellular and Tissue-Based Products (HCT/Ps),” dated August 2007 (Ref. 1).
Chagas disease is caused by the protozoan parasite, T. cruzi. The disease is found primarily in Mexico and Central and South America; the pathogenic agent has rarely been reported to cause human infection in the United States (U.S.) by natural vector transmission. Natural infections are transmitted mainly when the feces of certain blood sucking insects (triatomine bugs, commonly referred to as kissing or chinch bugs) that harbor the infection are rubbed into a bug bite, other wound, or directly into the eyes or mucous membranes. Current estimates are that at least 11 million persons in Mexico and Central and South America carry the parasite chronically and could present a potential source of infection should they become donors. The presence of the pathogenic agent in U.S. and Canadian donors is increasing due to immigration of infected individuals from endemic areas. Some experts estimate that there may be as many as 100,000 persons unknowingly infected with T. cruzi, who reside in the U.S. and Canada.
At the September 1989 Blood Products Advisory Committee (BPAC) meeting, the committee recommended testing donors of Whole Blood and blood components for Chagas disease when a suitable test became available. In December 2006, FDA granted a license to one manufacturer of an ELISA test system for the detection of antibodies to T. cruzi in individual living blood and HCT/P donors. Since the end of January 2007, a number of blood centers representing a large proportion of U.S. blood collections have been testing donors using this licensed assay. In February 2009, FDA licensed this ELISA test system for the detection of antibodies to T. cruzi in cadaveric (non-heart beating) HCT/P donors.
Blood donations from individuals from endemic areas are the primary source of risk for T. cruzi infection from transfusion. Studies in the mid-1990s (Ref. 1) estimated that the rate of seropositive blood donors in the U.S. ranged from 1 in 5400 to 1 in 25,000, depending on where the studies were conducted. However, more recent studies suggest that these rates have increased in the areas where donor testing has been performed over a period of time. For example, a rate of 1 in 2000 was found recently in the Los Angeles metropolitan area.
Studies also have looked at the rate of transfusion transmission from T. cruzi antibody-positive individuals. Published lookback studies in the U.S. and in Mexico of 22 transfusion recipients of seropositive donations, identified five of these recipients (22.7%) who later tested positive for antibodies suggesting transfusion transmission of T. cruzi (Refs. 18, 23 and 24). This transmission rate of 22.7% is consistent with the literature from Latin America on rates of blood-borne transmission from seropositive donors in Mexico and Central and South America.
There is a risk of transmission of T. cruzi by HCT/Ps and there has been sufficient incidence and/or prevalence to affect the potential donor population.
The World Health Organization recommends that:
T. cruzi infections can be fatal or life-threatening, result in permanent impairment of a body function or permanent damage to a body structure, and/or necessitate medical or surgical intervention to preclude permanent impairment of a body function or permanent damage to a body structure.
Appropriate screening measures have been developed for T. cruzi, such as the medical history interview. A donor screening test for T. cruzi has been licensed and labeled for use in testing blood specimens from living and cadaveric donors of HCT/Ps. You must use a donor screening test for T. cruzi that is specifically labeled for cadaveric specimens instead of a more generally labeled donor screening test when applicable and when available (21 CFR 1271.80(c)).
The FDA recommend testing of all donations of allogeneic units of blood using a licensed test for antibodies to T. cruzi. You must follow the regulations under
21 CFR 610.40(d) for determining when autologous donations must be tested.
The FDA recommend that all donors who are repeatedly reactive on a licensed test for T. cruzi antibody or who have a history of Chagas disease be indefinitely deferred and notified of their deferral.
At this time, there is no FDA licensed supplemental test for antibodies to T. cruzi that can be used for confirmation of true positive screening test results.
The FDA recommend that donors who are repeatedly reactive using a licensed test for antibodies to T. cruzi be informed about the likelihood and medical significance of infection with T. cruzi.
Because the licensed test has demonstrated some reactivity in donors infected with pathogens other than T. cruzi, the FDA recommend that medical follow up be considered for donors who are repeatedly reactive by the licensed test for antibodies to T. cruzi but who have no apparent basis for exposure to T. cruzi or who have negative results on more specific medical diagnostic tests.
We recommend that blood components from repeatedly reactive index donations be quarantined and destroyed or used for research.
Within 3 calendar days after a donor tests repeatedly reactive by a licensed test for T. cruzi antibody, you should:
In addition, when you identify a donor who is repeatedly reactive by a licensed test for T. cruzi antibodies and for whom there is additional information indicating risk of T. cruzi infection, such as geographical risk for exposure in an endemic area, or medical diagnostic testing of the donor, we recommend that you:
Under 21 CFR 1271.75(d), you must determine to be ineligible any potential donor who is identified as having a risk factor for or clinical evidence of relevant communicable disease agents or diseases. Ineligible potential donors include those who exhibit one or more of the following conditions or behaviors.
If you would like more detail in this area please get in touch with Damien Bové damien.bove@idaconsultants.com
Damien Bové works as a drug development consultant (pharmaceutical or biotechnology) and regulatory consultant, we work with our clients to define a drug development target, define a drug development strategy, define a regulatory strategy or define a commercial strategy. Our clients are generally raising funds or looking to license out their technology and we help them achieve it. If you want to know more don’t hesitate to get in touch.
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Posted in biotechnology, manufacturing, regulatory
Tagged biotech, BLA, chagas disease, development, ELISA, FDA, guidance, HCT, t.cruzi, whole blood and blood components.
Drug Regulators FDA publish New Guidance – Postmarketing Adverse Event Reporting for Nonprescription Human Drug Products Marketed Without an Approved Application.
This document provides guidance to industry on postmarketing serious adverse event reporting for nonprescription (over-the-counter (OTC)) human drug products marketed without an approved application. In particular, this document gives guidance on (1) the minimum data elements that should be included in a serious adverse event report, (2) the label that should be included with the report, (3) reporting formats for paper and electronic submissions, and (4) how and where to submit the reports.
The person who first notifies the responsible person about an adverse drug event is the reporter. Reporters can include patients, relatives of patients, consumers, doctors, pharmacists, other health care practitioners, or other individuals.
Reporters convey information on adverse events to the responsible person by various means, including phone, the Internet, fax, e-mail, or regular mail. Based on the information from the reporter and any other information received or obtained on the adverse event, the responsible person completes an ICSR in one of the formats described in section V of this document and submits it to FDA.
The quality of reports of serious adverse events submitted to FDA is critical for appropriate evaluation of the relationship between the product and adverse event(s).
In order for FDA to avoid duplication, interpret significance, facilitate follow-up, and detect fraud, at a minimum, the four data elements listed in the bullets below should be included in any serious adverse event report for an OTC drug product that is marketed without an approved application:
The responsible person should actively seek information on any minimum data element not initially provided by the reporter. The responsible person should not submit a report on the incident to FDA unless and until each minimum data element is obtained. FDA does not intend to take enforcement action for failure to submit a report for a serious adverse event where, after due diligence, the responsible person is unable to obtain one or more of the four minimum data elements. The responsible person should maintain records of the event information and its efforts to obtain the basic elements for an individual report in its files.
A serious adverse event, as defined in section 760(a)(3) of the Act, must have one or more of the following patient outcomes or, based on reasonable medical judgment, require a medical or surgical intervention to prevent one of the following patient outcomes:
The ICSR must be submitted within 15 business days of receipt of the report of the serious adverse event received through the address or phone number on the label (section 760(c)(1) of the Act). The date the responsible person receives the four basic elements (i.e., identifiable patient, identifiable reporter, suspect drug, serious adverse event) is Day 0 of the 15-business-day time clock and should be entered into item G.4 of FDA Form 3500A or its electronic equivalent.
Each ICSR of a serious adverse event associated with an OTC drug marketed in the United States without an approved application must be accompanied by a copy of the label on or within the retail package of the drug (see section 760(b)(1) of the Act).
If you would like more detail in this area please get in touch with Damien Bové damien.bove@idaconsultants.com
Damien Bové works as a drug development consultant (pharmaceutical or biotechnology) and regulatory consultant, we work with our clients to define a drug development target, define a drug development strategy, define a regulatory strategy or define a commercial strategy. Our clients are generally raising funds or looking to license out their technology and we help them achieve it. If you want to know more don’t hesitate to get in touch.
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Posted in clinical, marketing, regulatory
Tagged AER, FDA, ICSR, Individual case safety report, postmarketing adverse event
This guidance provides revised recommendations on what chemistry, manufacturing, and controls (CMC) information to include regarding the reporting, identification, and qualification of impurities in drug substances produced by chemical synthesis when submitting:
The guidance also provides recommendations for establishing acceptance criteria for impurities in drug substances.
The following types of drug substances are not covered in this guidance:
In November 1999, FDA published the first version of this guidance. As a result of changes to recommendations on impurities in drug substances for new drug applications (NDAs), which the International Conference on Harmonisation (ICH) included in the guidance for industry on Q3A Impurities in New Drug Substances (Revision 1) (Q3A(R)) in 2003. FDA believes that much of the content of the Q3A(R) guidance applies to ANDAs. See especially sections I through V and the Attachment, Thresholds.
Applicants submitting ANDAs, DMFs, including type II DMFs, and ANDA supplements for changes in the synthesis or processing of a drug substance are required to submit the specifications necessary to ensure the identity, strength, quality, and purity of the drug substance. Submissions should list impurities and set acceptance criteria for those impurities in the drug substance specifications.
Where applicable, the drug substance specification should include a list of the following types of impurities:
In establishing impurity acceptance criteria, the first critical consideration is whether an impurity is specified in the United States Pharmacopeia (USP). If there is a monograph in the USP that includes a limit for a specified impurity, we recommend that the acceptance criterion be set no higher than the official compendial limit. If a limit for a specified impurity does not exist in the USP, we recommend that you qualify the impurity by comparing it to the observed amounts of the impurity in the reference listed drug product (RLD). In some circumstances, the acceptance criterion may need to be set lower than the qualified level to ensure drug substance quality. For example, if the level of a metabolite impurity is too high, other quality attributes, like potency, could be seriously affected.
Qualification is the process of acquiring and evaluating data that establish the biological safety of an individual impurity or a given impurity profile at the level(s) being considered. When appropriate, we recommend that applicants provide a rationale for establishing impurity acceptance criteria that includes safety considerations.
An impurity is considered qualified when it meets one or more of the following conditions:
Recommended qualification thresholds based on the maximum daily dose of the drug substance are provided in Q3A(R). When these qualification thresholds are exceeded, we recommend that impurity levels be qualified. In some cases, it may be appropriate to increase or decrease the threshold for qualifying impurities.
If you would like more detail in this area please get in touch with Damien Bové damien.bove@idaconsultants.com
Damien Bové works as a drug development consultant (pharmaceutical or biotechnology) and regulatory consultant, we work with our clients to define a drug development target, define a drug development strategy, define a regulatory strategy or define a commercial strategy. Our clients are generally raising funds or looking to license out their technology and we help them achieve it. If you want to know more don’t hesitate to get in touch.
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Posted in manufacturing, regulatory
This guidance provides information on the implementation of new section 505(o) of the Federal Food, Drug, and Cosmetic Act (the Act) (21 U.S.C. 355(o)), added by section 901 of the Food, and Drug Administration Amendments Act of 2007 (FDAAA). Section 505(o) authorizes FDA to require certain postmarketing studies and clinical trials2 for prescription drug and biological products approved under section 505 of the Act or section 351 of the Public Health Service Act (the PHS Act) (42 U.S.C. 262).
In the past, FDA has used the term postmarketing commitment (PMC) to refer to studies (including clinical trials), conducted by an applicant after FDA has approved a drug for marketing or licensing, that were intended to further refine the safety, efficacy, or optimal use of a product or to ensure consistency and reliability of product quality. These PMCs were either agreed upon by FDA and the applicant or, under certain circumstances, required by FDA. Prior to the passage of FDAAA, FDA required PMCs in the following situations:
Section 506B of the Act provides FDA with additional authority to monitor the progress of a PMC by requiring the applicant to submit a report annually providing information on the status of the PMC.
FDA May Require Applicants to Conduct Studies and Clinical Trials. Section 505(o) of the Act authorizes FDA to require postmarketing studies or clinical trials at the time of approval or after approval if FDA becomes aware of new safety information.
Applicants Are Required to Report on the Status of Studies and Clinical Trials, this information must include:
The Guidance goes on in detail to discuss the regulations and how the FDA intends to interpret them, this guidance is for comment and the FDA would like to hear from you.
If you would like more detail in this area please get in touch with Damien Bové damien.bove@idaconsultants.com
Damien Bové works as a drug development consultant (pharmaceutical or biotechnology) and regulatory consultant, we work with our clients to define a drug development target, define a drug development strategy, define a regulatory strategy or define a commercial strategy. Our clients are generally raising funds or looking to license out their technology and we help them achieve it. If you want to know more don’t hesitate to get in touch.
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Posted in clinical, regulatory, Uncategorized
Tagged 505(o), FDA, FDAAA, PMR, post marketing requirements, regulatory
A guest report from Three Circles Consulting – Matthew Theobald - Report Site we publish guest articles if you have on of interest then get in touch.
Executive Summary
Research into the patterns of project variance (deviation from initial plans) across the biomedical sector has identified four recurring root causes.
A recently published discussion paper presents the interim findings of the research, highlights the actual impacts of the variances and presents a research led model to increase your project success.
The research involved senior executives from seventeen organisations within the biomedical sector with experience of project decision making, sponsorship or leadership roles. Projects examined ranged from process improvements, transfer of manufacturing site, through new product development and new facility builds to IT system implementations at local and multiple site levels.
A thorough analysis of the research data revealed four distinct sets of root causes.
The People set was by far the largest set of recurring causes of variance, significant overlaps were observed between this and each of the other three sets.
The paper describes the key causes of variance in each set, uses examples to illustrate their effects and provides salient quotes to describe the impacts felt by organisations.
Variances can have a catastrophic effect on both a project and the organisation. The impacts of project variances include:
Minimising and managing variance are key to delivering projects that satisfy customer expectations, within known time periods and costs.
Where projects are successful and low levels of variance observed, four domains were evident. To avoid the impacts detailed above, these discrete areas should be considered in the set up and running of any project. The discussion paper describes several practical measures that can be applied to gauge and reduce project vulnerability to the causes of variance.
Posted in biotechnology, report
the FDA publishes FAQ – Guidance for Institutional Review Boards (IRBs) Frequently Asked Questions – IRB Registration This guidance is intended to assist institutional review boards (IRBs) in complying with the new requirement for IRB registration. This requirement is an amendment to Part 56, Institutional Review Boards, (21 CFR 56.106), that requires each IRB in the United States (U.S.) that reviews FDA-regulated studies to register. IRB registration information is entered into an Internet-based registration system maintained by the Department of Health and Human Services (HHS). This system is a modification of the one used by the Office for Human Research Protections (OHRP) for registration of IRBs that are designated by institutions under Federalwide Assurances (FWAs). OHRP has issued a similar rule requiring IRBs designed under FWAs to register or update their registration information at this modified site. (See 74 FR 2399 (Jan. 15, 2009))
If you would like more detail in this area please get in touch with Damien Bové damien.bove@idaconsultants.com
Damien Bové works as a drug development consultant (pharmaceutical or biotechnology) and regulatory consultant, we work with our clients to define a drug development target, define a drug development strategy, define a regulatory strategy or define a commercial strategy. Our clients are generally raising funds or looking to license out their technology and we help them achieve it. If you want to know more don’t hesitate to get in touch.
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Posted in clinical, regulatory
Tagged clinical trials regulations, FDA, Internal review board
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The House of Lords has publishes the “Science and Technology Committee 2nd Report of Session 2008–09 Genomic Medicine Volume I: Report”
Modern, effective healthcare rests upon centuries of scientific advances and innovation that have been shown in clinical trials and other studies to prevent, cure or alleviate human disease. Every so often, a scientific advance offers new opportunities for making real advances in medical care. From the evidence given to this inquiry, we believe that the sequencing of the human genome, and the knowledge and technological advances that accompanied this landmark achievement, represent such an advance.
The 2003 White Paper, Our inheritance our future, recognised the potential impact of genetics and the genome project on our lives and our healthcare, and the importance of preparing the National Health Service (NHS) to be able to respond to this new knowledge. In our inquiry, we have investigated these many aspects of genomic medicine, and make recommendations to ensure that the challenges afforded by advances in genomic science are met and the opportunities exploited. If our recommendations are taken forward, we believe that the UK will benefit in terms both of wealth generation and of improved health of the population.
If you would like more detail in this area please get in touch with Damien Bové damien.bove@idaconsultants.com
Damien Bové works as a drug development consultant (pharmaceutical or biotechnology) and regulatory consultant, we work with our clients to define a drug development target, define a drug development strategy, define a regulatory strategy or define a commercial strategy. Our clients are generally raising funds or looking to license out their technology and we help them achieve it. If you want to know more don’t hesitate to get in touch.
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Posted in biotechnology, regulatory, report
The European Commission has published draft guidance for comment on “Detailed guidance for the request for authorisation of a clinical trial on a medicinal product for human use to the competent authorities, notification of substantial amendments and declaration of the end of the trial” Contributions should be sent by e-mail to entr-pharmaceuticals@ec.europa.eu on 8 September 2009 at the latest.
The scope of this guideline is the scope of Directive 2001/20/EC. Directive 2001/20/EC applies to all interventional clinical trials involving medicinal products as defined in Article 1(2) of Directive 2001/83/EC of the European Parliament and of the Council of 6 November 2001 on the Community code relating to medicinal products for human use (hereinafter “Directive 2001/83/EC”). This includes interventional clinical trials involving:
The Guidance is too large to give a detailed review here but I will try and pull out the most interesting sections.
The applicant should submit and sign a covering letter with the application. Its heading should contain the EudraCT number and the sponsor protocol number with a title of the trial. In the covering letter, the applicant should draw attention to peculiarities of the trial.
Before submitting an application to the national competent authority, the sponsor should obtain a unique EudraCT number from the EudraCT database by the procedure described in the Detailed guidance on the European clinical trials database.
The application form is accessible via the internet by the procedure described in the Detailed guidance on the European clinical trials database. The application form should uniquely identify the clinical trial and the organisations and key individuals responsible for the conduct of the trial.
According to Article 2(h), 1st period, of Directive 2001/20/EC, the protocol is “a document that describes the objective(s), design, methodology, statistical
considerations and organisations of a trial.”
The content and format of the protocol should comply with Section 6 of the Community guideline on Good Clinical Practice (CPMP/ICH/135/95).
According to Article 2(g) of Directive 2001/20/EC, the investigator’s brochure (“IB”) is “a compilation of the clinical and non-clinical data on the investigational medicinal product or products which are relevant to the study of the product or products in human subjects.” A request for authorisation has to be accompanied with an IB.
The content, format and procedures for updating the IB has to comply with Article 8(1) of the Commission Directive 2005/28/EC laying down principles and detailed guidelines for good clinical practice as regards investigational medicinal products for human use, as well as the requirements for authorisation of the manufacturing or importation of such products (hereinafter referred to as Directive 20005/28/EC) and with the Community guideline on Good Clinical Practice (CPMP/ICH/135/95).
Article 2(d) of Directive 2001/20/EC defines an IMP as follows: “[A] pharmaceutical form of an active substance or placebo being tested or used as a reference in a clinical trial, including products already with a marketing authorisation but used or assembled (formulated or packaged) in a way different from the authorised form, or when used for an unauthorised indication, or when used to gain further information about the authorised form.”
The IMP Dossier (“IMPD”) gives information to justify the quality of any IMP (i.e. including reference product and placebo) to be used in the clinical trial. It should also provide data from non-clinical studies and the previous clinical use of the IMP or justify in the application why information is not provided.
The sponsor has the possibility to submit a simplified IMPD if the information can be made available by referring to other submissions.
Medicinal products used in the context of a clinical trial and not falling within the definition of IMP are non-investigational medicinal products (“NIMPs”). The “borderline” between IMPs and NIMPs is described in the Guidance on Investigational Medicinal Products (IMPs) and other medicinal products used in Clinical Trials. It is strongly recommended that NIMPs with marketing authorisation in the Member State concerned are used for these purposes when possible. When this is not possible, the next choice should be NIMPs with marketing authorisation in another Member State. A SmPC for each NIMP with a marketing authorisation should be submitted with the clinical trials application dossier.
Notification/submission for information40 is only obligatory if the amendment is substantial or otherwise significant. Directive 2001/20/EC does not require notification of non-substantial amendments.
Article 10 (c) of Directive 2001/20/EC reads as follows: “Within 90 days of the end of a clinical trial the sponsor shall notify the competent authorities of the Member State or Member States concerned and the Ethics Committee that the clinical trial has ended. If the trial has to be terminated early, this period shall be reduced to 15 days and the reasons clearly explained.”
“End of the trial” is not defined in Directive 2001/20/EC. The definition of the end of the trial should be provided in the protocol and any change to this definition for whatever reason should be notified as a substantial amendment. In most cases it will be the date of the last visit of the last patient undergoing the trial. Any exceptions to this should be justified in the protocol.
The sponsor should make an end of trial declaration using the form published in Volume 10 of Eudralex – the Rules Governing Medicinal Products in the European Union
The clinical trial summary report is part of the end of trials notification. However, the clinical trial summary report can be submitted subsequently to the end of trials notification.
If a new event occurs after the termination of the trial that is likely to change the risk/benefit analysis of the trial and could still have an impact on the trial participants, the sponsor should notify the national competent authority and Ethics Committee of the Member State concerned and provide a proposed course of action.
Details of the Table of Contents of the Common Technical Document (CTD, eCTD) are given in the appendix.
If you would like more detail in this area please get in touch with Damien Bové damien.bove@idaconsultants.com
Damien Bové works as a drug development consultant (pharmaceutical or biotechnology) and regulatory consultant, we work with our clients to define a drug development target, define a drug development strategy, define a regulatory strategy or define a commercial strategy. Our clients are generally raising funds or looking to license out their technology and we help them achieve it. If you want to know more don’t hesitate to get in touch.
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Posted in clinical, regulatory
Tagged authorisation, Clinical trials regualtions, CTD, eCTD, EU, notification
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