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Drug Regulators, EMA, Publish Draft Guidance on the Use of Pharmacogenetic Methodologies in the Pharmacokinetic Evaluation of Medicinal Products

admin — Wed, 16 Jun 2010 08:33:15 +0000

Drug Regulators, EMA, Publish Draft Guidance on the Use of Pharmacogenetic Methodologies in the Pharmacokinetic Evaluation of Medicinal Products.

Full Text here

This guideline addresses the influence of pharmacogenetics on drug pharmacokinetics, encompassing considerations and requirements for the design and conduct of investigations during drug development. In particular, guidance is given regarding studies required and recommended at different phases of drug development to ensure satisfactory efficacy and safety in pharmacogenetic subpopulations that have variable systemic exposure of active substances.

The pharmacokinetics of many medicinal products is prone to interindividual variability, which is caused by several factors such as gender, age, weight, renal and hepatic function, and genetics. In recent years, a rapid development in our understanding of the influence of genes on interindividual differences in drug action has occurred. This development encompasses the area of pharmacogenomics, including pharmacogenetics, where interindividual variability in genes influencing or predicting the outcome of drug treatment (e.g., genes encoding drug transporters, drug metabolising enzymes, drug targets, biomarker genes) is studied in relation to efficacy of drug treatment and adverse drug reactions. A great deal of this interindividual variability is caused by genetic polymorphism, i.e. the occurrence in the same population of multiple allelic states. Genetic variations are demonstrated by the identification of Single Nucleotide Polymorphisms (SNPs), insertions/deletions and variation in gene copy number (copy number variation, CNV).

With respect to pharmacokinetics, the highest level of polymorphism is found in genes involved in drug metabolism; phase I metabolism of approximately 40% of clinically used drugs is due to polymorphic enzymes. Currently, the most important polymorphic enzymes are the cytochrome P450 enzymes such as CYP2C9, CYP2C19 and CYP2D6. Subjects who have extensive and poor metabolising capacity for these enzymes are present in the general population. For CYP2D6, besides the poor metaboliser phenotype, the ultrarapid metaboliser phenotype is relevant as well. With respect to phase II enzymes, the genetic variability of UDP-glucuronosyltransferases, N-acetyltransferase-2 and some methyltransferases has been linked to interindividual pharmacokinetic variability. The metabolising enzymes account for 80% of the drugs which currently include pharmacogenetic data in their labelling.

Among the major clinically relevant issues is pharmacogenetic variability causing increased or decreased metabolism of the parent drug and the subsequent formation of active or toxic substances. Decreased metabolism can cause too high levels of the parent drug and adverse drug reactions. Elevated drug metabolism can cause loss of response or, in case of prodrug activation, too high levels of the bioactive compound.

The interindividual genetically linked differences in pharmacokinetics may cause, clinically, very relevant alterations in drug action. Optimal efficacy is dependent on appropriate dosing, often based on the specific genotype. Thus, the effective dose may vary greatly due to increased or decreased drug elimination rate. For instance, due to CYP2D6 polymorphism, the rate of hepatic metabolism of drugs which are substrates for this enzyme can vary 1000-fold between individuals. Among many antidepressants and antipsychotics, the plasma levels of the drug at the same dosage often vary 5-20-fold. A 9-fold higher risk of suicide has been reported among ultrarapid metabolisers of CYP2D6 and there are also many reports of increased frequency of adverse drug reactions among subjects with the poor metaboliser phenotype, due to increased systemic exposure of the parent drug. Furthermore, increased side effects after treatment with analgesic drugs, which are activated by CYP2D6, are seen among ultrarapid metabolisers. The efficacy of prodrugs which are activated by polymorphic enzymes varies depending on the pharmacogenetics of the patients. An example of this is clopidogrel, for which an increased frequency in serious side effects due to excessive prodrug activation has been seen in patients with increased formation of the active metabolite and a corresponding lack of effect in subjects without the appropriate enzyme. Dosing of some important anticoagulants is dependent on the CYP2C9 genotype of the patient and the platelet inhibition action of some drugs is dependent on the CYP2C19 genotype. Overall, it can be estimated that 20-25 % of the efficacy of all drug treatment is significantly affected by interindividual differences in genes encoding drug metabolising enzymes.

At present, an increasing proportion of lead compounds selected for further development are metabolised by enzymes or transported by transporter proteins upon which the impact of pharmacogenetics is unknown. New technologies, such as rapid genome sequencing, whole genome wide association studies (GWAS) and targeted absorption, distribution, metabolism and excretion (ADME) gene SNP/CNV analyses, are expected to have an integral role in clinical drug development in the future.

Until now, it has been difficult to transfer knowledge of the effect of polymorphism into specific recommendations in affected genetic subpopulations1. In this respect, genetic subpopulations have been treated differently than other subpopulations or circumstances in which the exposure of active or toxic substances is increased. The aim of including pharmacokinetics-related pharmacogenetics in drug development is to evaluate whether exposure in genetic subpopulations is different to such an extent that this would require a change in the posology or treatment recommendation of the drug for the specific subpopulation. This document, therefore, aims to clarify the studies needed to investigate these issues.

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Damien Bové is THE Drug Development and Regulatory Consultant (pharmaceutical or biotechnology), I work with my 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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Drug Regulators, EMA (EMEA), Publish Draft Guidance on the Use of PharmacoGenetic Methodologies in the Pharmacokinetic Evaluation of Medicinal Products

admin — Sat, 29 May 2010 08:28:42 +0000

Drug Regulators, EMA (EMEA), Publish Draft Guidance on the Use of PharmacoGenetic Methodologies in the Pharmacokinetic Evaluation of Medicinal Products.

Full Text Here

In recent years, journal articles have been published describing specific polymorphisms in drug transporters and their possible effect on the efficacy and safety of medicinal products. However, in the majority of cases the influence of transporter polymorphism on drug pharmacokinetics has not yet been clarified. The effect of transporter polymorphism on drug pharmacokinetics is thought to be of less importance, or is still unknown, compared with polymorphic enzymes. This is partly due to the fact that the role of specific transporters in vivo is difficult to quantify due to the lack of specific inhibitorsand the polymorphism seen in the transporters is often substrate specific in its effects. The possibility of transporter polymorphism as a cause of altered pharmacokinetics must, however, always be considered in all phases of drug development. It is anticipated that this area will expand a great deal in the near future, as knowledge of the role of drug transporters is rapidly developing.
At present, an increasing proportion of lead compounds selected for further development are metabolised by enzymes or transported by transporter proteins upon which the impact of pharmacogenetics is unknown. New technologies, such as rapid genome sequencing, whole genome wide association studies (GWAS) and targeted absorption, distribution, metabolism and excretion (ADME) gene SNP/CNV analyses, are expected to have an integral role in clinical drug development in the future.
Until now, it has been difficult to transfer knowledge of the effect of polymorphism into specific recommendations in affected genetic subpopulations1. In this respect, genetic subpopulations have been treated differently than other subpopulations or circumstances in which the exposure of active or toxic substances is increased. The aim of including pharmacokinetics-related pharmacogenetics in drug development is to evaluate whether exposure in genetic subpopulations is different to such an extent that this would require a change in the posology or treatment recommendation of the drug for the specific subpopulation. This document, therefore, aims to clarify the studies needed to investigate these issues.

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Liver Toxicity, FDA DILI Regulations Require Interpretation

admin — Fri, 20 Nov 2009 16:15:26 +0000

Save Your Project from an Unjust Death

Signs of liver toxicity from experimental results can mean that a project is killed or investors walk away, but this is often an inappropriate response. Liver toxicity is a highly complex issue and in an attempt to provide some light on the issue the FDA has recently published guidelines on Drug Induced Liver Injury (DILI). These guidelines set the regulatory standard and take a very pragmatic position on liver tox and encourage industry to likewise take a pragmatic view.

However Companies need help in reviewing data and taking that pragmatic view, in response to this IDA consultants have made available a number of experts to provide the review that will help you:

DON’T kill your project without good cause
DO understand what the data actually means
PLACE your results in therapeutic context
REASURE investors with expert opinion

Liver Toxicity Data Review and Expert Opinion

Worrying liver tox results can come from a number of sources:

Pre-Clinical
Clinical
In-Vitro
Metabolite Studies
Class effects

IDA consultants has arranged a group of high caliber experts, all with masses of FDA and EMEA experience who can review your data and make recommendations that put it in context of the DILI regs and the therapeutic / technology risk profile:

PK/PD
Standards of Care
Co-morbidities
Product specific factors
Risk/Benefit ratio

Re-capture the value in your project

The outcomes of this work is an expert report that puts the Liver tox data in context, and puts the value back in your technology. The expert report is of a standard suitable for investors, and regulators alike.

This review can save your project from an un-just death, and is available from £7000. The first step is to organize a Free review so you can understand the options available for your technology without spending a penny.

Get in touch for your free Consultation.

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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recombinant vaccines for the prevention and treatment of infectious disease, and provides guidance on quality, non-clinical and clinical aspects.

Drug Development Guidance – FDA publish Drug Induced Livery Injust Evaluation Guidance

admin — Wed, 19 Aug 2009 13:05:52 +0000

Drug Regulators, FDA, Publish Drug Development Guidance

Drug-Induced Liver Injury: Premarketing Clinical Evaluation

Introduction

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.

Background

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.

Signals of DILI and Hy’s Law

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:

The drug causes hepatocellular injury, generally shown by a higher incidence of 3-fold or greater elevations above the ULN of ALT or AST than the (nonhepatotoxic) control drug or placebo
Among trial subjects showing such AT elevations, often with ATs much greater than 3xULN, one or more also show elevation of serum TBL to >2xULN, without initial findings of cholestasis (elevated serum ALP)
No other reason can be found to explain the combination of increased AT and TBL, such as viral hepatitis A, B, or C; preexisting or acute liver disease; or another drug capable of causing the observed injury

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

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FDA introduces new Rules of IRB Registration

admin — Thu, 23 Jul 2009 08:34:14 +0000

Drug Regulators, FDA, Introduce New IRB registration Rules

Clinical Trials Regulations have been changed following on from the Coast scandal reported in this site (article). I have just received this update from the ICR

The FDA IRB Registration Rule is effective Tuesday, July 14, 2009. All IRBs reviewing FDA-regulated research must register between July 14 and September 14, 2009. IRBs that review FDA-regulated studies and that are not already in the OHRP IRB registration system must submit an initial registration. If your IRB is already registered in the OHRP system, the registration information must be updated to include all of the information required by the FDA IRB Registration Rule. Please see the guidance referenced below for more information.

This registration will be accomplished through a modified version of the database used by the Office for Human Research Protections (OHRP).Please note: the database for electronic submission of IRB registrations will not be available until July 14, 2009.

If you would like more detail in this area please get in touch with Damien Bové damien.bove@idaconsultants.com

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The Impact of the Clinical Trails Directive

admin — Mon, 06 Jul 2009 08:01:08 +0000

The impact of the clinical trials directive on clinical drug development

The impact of the clinical trials directive on clinical drug development has been evaluated by ICREL (Impact of Clinical Research of European Legislation) who have just published their report (HEALTH-F1-2007-201002). When the clinical trials directive was brought in in 2001, its main objectives were:

Protection of human subjects in clinical research
Implementation of the Good Clinical Practice (GCP) standard in all clinical trials with medicinal products
Harmonised procedures for clinical trials authorisation from competent authorities and ethics committees
Central collection of information on clinical trials activities and safety results

Implementation of the directive into national legislation of all 27 EU member states was completed in 2006. Principles like Clinical Trial Authorisation by the competent authority and favourable opinion of a single ethics committee within defined maximum time-lines led to significant harmonisation of the clinical trial approval process. However, differences in interpretation of the modalities for this and other processes harmonised by the CTD, led to even higher complexity levels – especially in the performance of multi-national clinical trials. Today, a sponsor of a clinical trial needs to have very detailed knowledge about every country’s national requirements for clinical trial authorisations from competent authorities and ethics committees and has to integrate the different requirements to the protocol and IMPD resulting from parallel submission in multi-national trials.

This FP7-funded ICREL project aimed at objectively measuring the impact of the clinical trials legislation on the key stakeholder groups “commercial and non-commercial
sponsors”, “competent authorities” and “ethics committees” in the European Union by providing:

objective information on positive and negative impact factors on clinical trials with medicinal products and on other types of clinical research
reliable figures on the impact of the legislation on the clinical research activity of big Pharma Industry -, SME- and academia-sponsored trials
evaluation of the resource, cost and effectiveness implication of the EU CTD implementation for all stakeholders
comparison of the success of national CTD implementation
consolidated conclusions on the findings amongst the stakeholders
dissemination of the conclusions to the public at large

The Results

The Results of the Clinical Trials Directive research was broken down by stake holder:

Competent Authorities

The vast majority (25 out of 28) of EU CAs participated in the survey. Two non-EU CAs from countries integrated within the EU regulatory system accepted to participate and provided responses.
Content and quality of the responses varied greatly and were obviously dependent on the time, resources and systems the CAs had available to compile the information
An impact on clinical research activity in the EU derived from the CTD implementation was apparent, though could not be readily confirmed from the available data
No negative impact of the CTD on commercial sponsors could be detected. The number of CTAs submitted by commercial sponsors increased slightly (+11%) between 2003 and 2007
Overall, a slight potential negative impact of the CTD on non-commercial sponsors was detected represented by a relative change of -25% of CTAs between 2003 and 2007, however, while some countries faced strong or even dramatic decreases other countries experienced an increase of non-commercial CTAs.
The number of substantial amendments and SUSAR reports increased strongly after CTD implementation
Average CTA timelines decreased after CTD implementation and were, in 2007, with 49 days clearly below the 60-day limit
The indisputably increased administrative burden imposed by the CTD on the evaluation process and supervision of CTAs was reflected by an increase in workforces and related costs which was paralleled by a raise in fees

Ethics Committees

Despite multiple contacts, the number of responding ECs was quite low
The overall number of positive opinions increased by 23% between 2003 and 2007, with especially strong increases in CTs with medical devices and radiotherapy as well as non interventional/observational studies
A huge increase in workload for ECs was observed since the implementation of the CTD, evidenced by not only the increase of opinions but also higher numbers of substantial amendments and SUSAR reports to ECs
The number of negative opinions issued by lead or central ECs increased between 2003 and 2007 in line with the overall increase of reviews. More than 25% of responding ECs did not have an appeal system in place in 2007, but in countries where an appeal system was in place, it was significantly more frequently used than in 2003
An increase in FTEs per EC was reported, however, the absolute numbers of employees per EC were still very low and often no clear differentiation was made between unpaid EC members and employees
More than half of the ECs did not involve external reviewers in assessing applications despite the increasing complexity of the CTAs
No differences could be detected in number of EC meetings and duration of review time per protocol between 2003 and 2007. However, the duration of the meetings increased slightly, but significantly
Fees charged by lead or central ECs to commercial sponsors, SMEs and orphan drug trial sponsors for review of protocol and substantial amendments increased significantly from 2003 to 2007, but the fee level was different for these categories. The fee for academic trials was much lower and increased only slightly. Non-lead ECs did not charge significantly lower fees than lead or central ECs
The annual budget of ECs increased by 50% between 2003 and 2007
In 2007 ECs received final report summaries for less than 20% of the reviewed protocols
60% of responding ECs had no patient representative in their membership
Especially non-lead/central ECs considered the procedure to generate a single opinion to be difficult

Commercial Sponsors

The overall number of commercially-sponsored clinical trials increased by about 30%, driven by increases seen in large and medium-sized companies
SMEs did not experience an increase but faced higher staff needs and related costs due to an increase in trial complexity
Areas of relatively stronger increases were clinical trials with biotechnology products and with orphan indications
Clinical trials were increasingly organized in more countries and more sites than before implementation of the CTD, however, the number of recruited patients increased only slightly
There was no shift detectable in the responding companies in the type of trial phases performed in 2003 and 2007. However, generic companies did not participate in the survey because they reportedly do not perform their bioequivalence trials in Europe anymore
Time lines for the overall protocol and substantial amendment approval process were extended by approximately 30%.
Need for staff increase for preparation and management of clinical trials as well as for pharmacovigilance tasks, need for investment required to adapt IT systems to the new safety reporting requirements, and an increase of subject indemnity insurance fees added to an overall increase in resources required for the performance of clinical trials in the new regulatory environment without a demonstrable impact on improving patient safety
In the opinion of commercial sponsors, the CTD has created a certain level of harmonisation of the clinical trials infrastructure in the EU, but as this harmonisation has not been sufficiently far-reaching, the complexity of clinical trials has increased

Non-Commercial Sponsors

According to this survey’s data, the major impact of the CTD on the NCS activities was reflected in a significant increase of the workload and timelines, i.e., an increase in the time period before the entry of the 1st patient. The CA data did not show significant changes in the overall number of clinical trials conducted by NCSs. Overall, the CTD was perceived as having introduced a partial harmonisation of procedures, but this positive effect was heavily counterbalanced by the general lack of harmonisation, the increase of the administrative burden and related costs. NCSs called for simplified and harmonised requirements and sound
risk based-approach
A great heterogeneity was observed in the responses rates, the number of missing values, and the trends arising from the data collected from NCSs. These reflected the great heterogeneity of the NCS organisations, reaching from large research organisations and well-organised structures to small structures with a lower level of cooperative and dedicated resources. The capacity of NCSs to log critical information needs to be improved
This survey was not designed for qualitative assessment of the impact of the CTD on the performance of future studies. The following questions need to be addressed: has the CTD improved patient protection and safety? What is the impact of the CTD on the quality of science: do we guarantee progress for patients in a timely manner? Can the nature of investigator-driven trials be preserved when independence from industry is threatened by the increasing burden of conducting such kinds of activities?
A re-evaluation of the situation with respect to the implementation of the CTD and its impact would need to be performed over a 3-year time frame in order to take advantage of a more complete EudraCT database. The systematic comparison with the situation in non-EU territories, e.g. US, Canada and Japan, should also be included.

Overall Conclusion and Recommendation

ICREL provided strong arguments supporting some of the recommendations proposed by various stakeholders in scientific journals, at the EC-EMEA conference on the Directive (2007) and in the ESF “Forward Looks on investigator-driven clinical trials” (2009).

A risk-based approach to regulation would result in a substantial reduction in workload and cost, particularly for academic institutions that run a number of low-risk studies using marketed drugs
Simplification of the Clinical Trial Authorisation process by the competent authorities through a single CTA for multi-national trials would reduce duplication of efforts and also save time, costs, and expertise
Harmonised practice in ethics committee requirements would facilitate and reduce the administrative burden of dossier submission, and changes in expedited SUSAR reporting to the ethics committees would alleviate their workload
Insurance coverage for clinical trials should be reconsidered at the EU level and adequate funding should be provided to institutions performing clinical trials to ensure capacity and expertise for all trial-related activities

The above coments are form the Executive Summary and I woudl advice anybody with an interest in teh area to read the full report which is available from the ICREL site.

If you would like more detail in this area please get in touch with Damien Bové damien.bove@idaconsultants.com

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recombinant vaccines for the prevention and treatment of infectious disease, and provides guidance on quality, non-clinical and clinical aspects.

A Thought Provoking Consideration of Surrogate Endpoints

admin — Tue, 19 May 2009 13:38:37 +0000

Surrogate endpoints are an essential part of the drug development professionals arsenal, without them many products would be too expensive and too long to be economically viable, but the challenge as ever is selecting those that are going to give you the best insight into your products utility, whilst being cost effective and timely. As with many things its “correlation does not mean necessarily causation” . I for one am happy to use surrogate endpoints, the regulators are happy for me to use them and the wider scientific community is happy for me to use them, but always bear in mind when your using a surrogate its just that a surrogate and does not tell you directly what is happening and there is always a risk associated with that.

I have just read a great article that puts this point across very well and is worthy of a read. When the Lights Go Out by Darshak Sanghavi at Slate.com why not have a read.

If you would like more detail in this area please get in touch with Damien Bové damien.bove@idaconsultants.com

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