Monthly Archives: May 2009

EMEA re-posts Points to Consider on Missing Data

Posted on May 29, 2009 by admin| Leave a comment

The EMEA has re-posted points to consider on missing data, this points to consider was formally adopted in 2001, however the EMEA has chosen to re post this on the website. It does not appear to have changed since its last posting.

The EMEA a considered missing data as a potential source of bias when analysing clinical trials, interpretation of the results of a trial is always problematic when the number of missing values is substantial. There are many possible sources of missing data, affecting either complete subjects or specific items, missing data violate the strict Intend To Treat principals: measurement of patient outcomes regardless of protocol adherence and analysis performed by treatment assigned, regardless of which treatment patients actually received. If missing values are handled simply by excluding any patients with missing outcomes from analysis, the following problems may affect the interpretation of the trial results.

The sample size and variability of outcomes affects the power of the clinical trial, power is greater the larger sample size and smaller variability. The reduction in the number of cases available for analysis, completeness of data add ot the resulting reduction of the statistical power.

Bias is the most important concern resulting from the missing data may affect: Designation of the treatment effect, The comparability of the treatment groups, The representativeness of the study sample in relation to the target population. Bias occurs in the estimation of the treatment effect when the relationship between missing this treatment outcomes exists. In most cases it is difficult or impossible to elucidate whether the relationship between missing values and unobserved outcome variable is completely absent. Thus it is sensible to adopt a conservative approach, considering missing values as potential sources of bias.

A possible way of handling incomplete data is to ignore them and perform statistical analysis with complete data only. However, complete case analysis violates intention-to-treat principal. More importantly it is subject to bias, and thus cannot become recommended as the primary analysis confirmatory trial.

The statistical analysis of the clinical trial requires imputation of values to those data that have not been recorded. Many techniques have been used for the imputation of missing data, but none of them can be considered as the gold standard in every situation. The guidance goes on to discuss the many options available:

To cope with situations where response collection is interrupted at one point, the widely used method is last observation carried forward. This method is likely to be acceptable if measurements are expected to be relatively consistent over time.

Best worst case imputation, assigning the worst possible value of the outcome to dropouts are a negative reason (treatment failed) and the best possible value to positive dropouts (kills), is another approach that can be considered, provided it is applied conservatively.

Another simple approach of inputting missing data is to replace the unobserved measurements by values derived from other sources. Possible sources include information from the same subject, from other subject of similar baseline characteristics, the predictive value from an empirically developed model, historical data, etc.

Most methods faced the risk of bias in the standard error downwards by estimating central value and ignoring its uncertainty. This risk can be avoided by some techniques based upon maximum likelihood methodology and with multiple imputation methods. Maximum likelihood methodologies have been proposed that imputation of missing values, as have multiple imputation methods. Maximum likelihood method strategies fit the model by an iterative process. Multiple input methods generate multiple copies of the original dataset replacing missing values by randomly generated values, and analysing is complete sets.

Unfortunately, there is no universally accepted methodological approach and the missing values.the best process of all is the avoidance of missing data in the first place.

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, medical report, regulatory

Tagged clinical, EMEA, guidance, missing data, regulatory, statistics

EMEA republish points to consider on clinical investigation of medicinal products used in the treatment of osteoarthritis

Posted on May 28, 2009 by admin| 1 Comment

The EMEA has republished points to consider on the clinical investigation of medicinal products used in the treatment of osteoarthritis, this was originally published in July 1998 however the EMEA has recently re-posted it on their website. The publication has not been altered since 1998. This concept paper presents guidance for clinical studies addressing pharmaceutical treatment of osteoarthritis only systemic products are addressd, topical remedies in particular and not dealt with in this paper and other rheumatic diseases are also not considered.

The concept paper starts by outlining the classification of anti-osteoarthritis therapies, these are medications that affect the symptoms and/or modify structures within the disease. The nomenclature currently proposed recognises 3 types of drugs acting on osteoarthritis: fast acting drugs that induce symptomatic relief, slow acting drugs that induce symptomatic relief and disease modifying drugs.

Due to the pathophysiological differences of osteoarthritis in different body parts the EMEA treats different body parts sa different indications for the purposes of results interpretation and product registration.

The paper also goes on to describe the primary and secondary efficacy endpoints for the different types of drug: symptom modifying drugs, largely rely on pain and function as primary endpoints. Structure modifying drugs rely on long-term outcomes such as necessity for joint replacement time to need surgery and long-term clinical performance (pain and disability).

The paper also includes guidance on clinical trial design for dose finding and therapeutic comparative trials: study population is given particular attention, as is concomitant interventions. The use of placebo and the choice of comparators is also addressed in the document as are safety considerations.

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

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Posted in clinical, regulatory

Tagged EMEA, guidance, osteoarthritis, regulatory

EMEA re-post Draft Guidance on the Clinical Evaluation of Anti-virals intended for HepC

Posted on May 27, 2009 by admin| 1 Comment

The EMEA has reposted draft guidance on the “Clinical Evaluation of Direct Acting Antivial Agents Intended for the Treatment of Chronic Hepatitis C”. the guidance was originaly posted in April 2008, but the EMEA has re-posted it. the contents don’t appear to have altered and in summary:

The guidlines are focused on testing new therapies as add-on to current gold standard (Pegalated-interferon alpha 2a and 2b).
A special concers is the high mutation rate of HepC with the attendant risk of selection of drug resistant variants.
Initial studies should enrol subjects naive to Standard of Care who do not have advanced fibrosis or HIV co-infection.
The next study coudl enrole patients with genotype 1 infections who have had a sub-optimal response to standard of care or relapsed.
Once effect of the add-on therapy have been described later studies can look at specific groups such astumour types, HIV infected patients and mornull responders to standard treatments

There is also discussion of epidemiology of infection quoting around 3% of the worlds population has been infected and around 200 million people at risk of developing serious liver morbidity. The natural course of infection is also discussed around 60 to 80% of infected individuals becoming chronic carriers.and after about 20 years 20 to 30% of them have progressed cirrhosis, the five-year risk of hepatic decompensation is around 15 to 20% and that of hepatocellular carcinoma around 10%.

Guidance is provided on the design of exploratory and confirmatory clinical studies considered to be of relevance for the evaluation of direct acting anti-hepatitis C compounds as add on to standard of care in different populations. Guidance is given on subjects characteristics and selection of subjects, guidance is also provided on genotyping, primary endpoints the recommendation in this case sustained virological response defined as undetectable virus RNA six months after completion of therapy. Secondary endpoints are also described, end of treatment response and time to confirmed undetectable viral load, rapid viral response and early viral response, liver histology guidance is also provided.

Guidance goes on to describe the pharmacokinetic studies that are required the pharmacodynamic studies that are required, the guidance then goes on to describe appropriate for one studies in special populations; transplant patients and studies in children.

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

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Posted in clinical, regulatory, Uncategorized

Tagged clinical, Efficacy, EMEA, HCV, regulatory

EU announces 246 million Euros of medical research funding and tells us what they are looking for in the next round

Posted on May 20, 2009 by admin| Leave a comment

The European Commission and the EFPIA announced on Monday that 15 research projects were selected to receive a total of 246 million Euros (US$333 million) in research funding made available through the Innovative Medicines Initiative (IMI). The selected projects will address the main causes of bottlenecks in the pharmaceutical R&D process.

the 15 projects will focus on the health issues such as diabetes, psychiatric disorders, severe asthma and pain. The Pharmaceutical industry provides 136 million Euros (US$184million) through provision of their resources, facilities, materials and staff, and the remaining 110 million Euros goes to other participants such as small businesses, patient groups and academic groups.

The next call for proposals, is in the autumn and they will be seeking products in Oncology, Chronic Inflammatory disease, among others.

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

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Posted in business, Fund raising

Tagged EFPIA, EMEA, EU, Funding, IMI

A Thought Provoking Consideration of Surrogate Endpoints

Posted on May 19, 2009 by admin| Leave a comment

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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Posted in clinical, regulatory

Tagged clinical development, surrogate endpoints

FDA guidance – Submission of Bioequivalence data for ANDA’s

Posted on May 18, 2009 by admin| 3 Comments

The FDA published this guidance back in April but we have just now had the time to review it.

This guidance is intended to assist applicants who are submitting abbreviated new drug applications (ANDAs) in complying with FDA’s new requirements for the submission of bioequivalence (BE) data.

FDA’s final rule on “Requirements for Submission of Bioequivalence Data” (the BE data rule) requires ANDA applicants to submit data from all BE studies the applicant conducts on a drug product formulation submitted for approval, including studies that do not demonstrate that the generic product meets the current bioequivalence criteria.

This guidance provides information on the following subjects:

The types of ANDA submissions covered by the BE data rule
A recommended format for summary reports of BE studies
The types of formulations FDA considers to be the same drug product formulation for
Different dosage forms based on differences in composition.

The important points of this guidance is that all studies must be submitted for ANDA applications and a format for those submissions is advised:

“For a suggested format for summary reports, please refer to the Office of Generic Drugs (OGD) Web page.6 The Division of Bioequivalence has developed model data summary tables in a concise format consistent with the ICH Common Technical Document (CTD). The tables, under the heading “Model Bioequivalence Data Summary Tables,” are available in Word and PDF formats. The FDA recommends that these table formats be used to organize the data for summary reports required by the BE data rule”

Drug Formulation

FDA amended the regulations to require an applicant to submit data from all BE studies conducted on the same formulation of the drug product submitted for approval.

“Same drug product formulation means the formulation of the drug product submitted for approval and any formulations that have minor differences in composition or method of manufacture from the formulation submitted for approval, but are similar enough to be relevant to the FDA’s determination of bioequivalence”

The guidance goes into greater detail on this point, this forms the bulk of the guidelines.

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

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Posted in clinical, formulation, regulatory

Tagged bioequivalence, FDA, Guidlines, Regulations

EMEA puts out a new concept paper – developing a guidline for the use of Pharmcogenomic Methodologies in the Pharmacokinetic Evaluation of Medicinal Products

Posted on May 15, 2009 by admin| Leave a comment

EMEA put out a concept paper on “The development of a guidline on the use of pharmacogenomic methodologies in the pharmacokinetic evaluation of medicinal products”

Background

In recent years there has been a rapid development regarding our understanding of the genetics behind interindividual differences in drug response, pharmacogenomics forms a major part of this research area, where interindividual variability in genes encoding drug transporters, and drug metabolising enzymes affects the systemic and target organ exposure of pharmacologically active substances, thereby affecting the efficacy obtained of drug treatment as well as the occurrence of adverse drug reactions. The highest abundance of genetic polymorphism is registered at the level of drug metabolism where approximately 40 % of phase I metabolism of clinically used drugs is catalysed by enzymes with polymorphisms known to have a marked impact on their function in vivo.

In light of the evolution and broad acceptance of genotyping methods, as well as increased experience in the use of such pharmacogenomic methodologies during drug development, the EMEA considered it appropriate to update and align this progress in a Guideline on this topic.

What the guideline hopes to achieve

The fundamental issues to be discussed in a proposed CHMP Guideline is how to implement pharmacogenetics affecting PK in drug development, how the pharmacokinetic variability arising from pharmacogenetic differences may best be determined, how to assess clinical relevance of the pharmacokinetic differences and recommendations on how to reflect these data in the labelling.

So if you have any interest in the topic you need to be getting in touch with the EMEA and register your interest.

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

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Posted in clinical, pre-clinical, regulatory

Tagged concept paper, EMEA, Guidlines, pharmacogenomics

Functional Foods Overstep the Claims – are Cheerios a drug? the FDA think so

Posted on May 14, 2009 by admin| 1 Comment

General mills the manufacture of Cheerios has been issued with a a warning letter from the FDA for “serious violations” of the FDC act in the label and labeling of Cheerios cereal, there lies a lesson in this for other companies making functional food claims.

the FDA claims that the following label claims make Cheerios an unapproved drug under FDC Act# 505(a), as they indicate that the cereal is intended to prevent, mitigate, and treat hypercholesterolemia.

“you can Lower Your Cholesterol 4% in 6 weeks”
“Did you know that in just 6 weeks Cheerios can reduce bad cholesterol by an average of 4 percent? Cheerios is … clinically proven to lower cholesterol. A clinical study showed that eating two 1 1/2 cup servings daily of Cheerios cereal reduced bad cholesterol when eaten as part of a diet low in saturated fat and cholesterol.”

And because the website is given on the packaging and that goes on to make more claims these are also treated as labelling. This is no new issue in the food industry but the FDA has done very little enforcement of the rules but that appears to be changing, is this a shot across the bows of the food industry.

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

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Posted in clinical, regulatory, Uncategorized

Tagged claims, FDA, functional foods, labeling

US governemet to spend US$1.1 billion on Evidence Based Medicine

Posted on May 13, 2009 by admin| Leave a comment

The US government has stirred up a hornets nest of debate with plans to spend US$1.1 billion on evidence based medicine studies, of comparative effectiveness research as they call it. They plan to give the money to the HHS, NIH, and the Agency for Healthcare Research and Quality to finance studies, and develop patient databases and other data-collecting tools.

There are a panel of government health experts currently holding public hearings to decide on the conditions to be investigated, it will be interesting to see how the big pharma PR machine comes into play with this process.

There are many groups in favour of this approach, medical researchers, consumer groups, unions, insurance companies who think it will eliminate ineffective treatments and reduce fedral spending, which was US$2.2 trillion in 2007, or 16% of US national gross domestic product.

However as to be predicted there are a number of pharmaceutical and medical device companies as well as medical trade groups who have expressed concern that the research could lead to rationed healthcare and inadequate treatment for some patients. Its an interesting development but as in Europe generally and the UK specifically we have been living in a world of evidence based medicine and NICE reviews its something we are very familiar with.

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

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Posted in business, Uncategorized

Tagged evidence based medicine, Funding, reaserch, USA

Pause in Normal Service

Posted on May 11, 2009 by admin| Leave a comment

There will be a pause in updates to this site, lasting approximately a week, as we move from one hosting provider to another, demand has caused some issues with the site that we intend to overcome with a move to a new hosting provider. However we will return will a whole series of articles on selling to the NHS looking at the processes, groups and the evidence bases needed, it will be good, plus there will be our usual array of new and interesting articles.

So stay tuned and we will be back soon with normal service.

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Posted in Uncategorized

FDA approves first ever Human drug from Geneticaly Engineered Animals

Posted on May 10, 2009 by admin| 1 Comment

FDA recently approved the first biological product made from genetically engineered animals. The product, called ATryn, is an anticoagulant used to prevent blood clots in patients with a rare disease known as hereditary antithrombin deficiency. These patients can develop blood clots during high-risk situations such as surgery and childbirth. The approval gives patients with this disease an important new treatment option.

ATryn is a therapeutic protein made from the milk of genetically engineered goats. These goats have had a segment of DNA introduced into their genes that causes the female goats to produce human antithrombin in their milk. FDA’s approval prohibits using these animals for food or feed, and also ensures that the genetic modification is not harming the animals. The manufacturer will continue to monitor the product’s safety, including the possible development of immune responses in patients who receive repeated ATryn treatments. The product is expected to be available in the second quarter of 2009.

Its a significant step, for the technology and the industry.

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

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Posted in biotechnology, regulatory

Tagged biological, Drug, FDA, Genetic Engineered

FDA Guidance for Industry – Intergrated Summaries of Effectivenss and Safety: Location within the Common Technical Document

Posted on May 4, 2009 by admin| Leave a comment

Yes even more FDA guidance this week, Guidance for Industry Intergrated Summaries of Effectivenss and Safety: Location within the Common Technical Document.

This new guidance focuses on where to place ISE and ISS documents within the structure of the CTD or eCTD. It does not outline in detail the content for the ISE and ISS. The content will be addressed in separate guidance’s.

This guidance is intended to clarify for industry where to include the integrated summary of effectiveness (ISE) and integrated summary of safety (ISS) when submitting applications in the common technical document (CTD) format. The guidance applies to applicants submitting new drug applications (NDAs) or biologic license applications (BLAs) to the Food and Drug Administration (FDA) in the CTD or the electronic common technical document (eCTD) format.

The ISE and ISS are not summaries but rather detailed integrated analyses of all relevant data from the clinical study reports that belong in Module 5. The FDA consider the ISE and ISS critical components of the clinical efficacy and safety portions of a marketing or licensing application. However there are other modules that need this data and the FDA is providing guidance where this information should be used.

the CDT/eCDT Module 2 contains several clinical sections that are summaries, these should in general follow the outline of the ISE and ISS. It should be noted that the model 2 section is limited to 400 pates and the typical ISS alone us often substantially larger, which in itself necessitates the need for editing. The section include:

2.5 Clinical Overview (aropund 30 pages)
- 2.5.4 Overview of efficacy
- 2.5.5 Overview of safety
2.7 Clinical Summary (50 to 400 pages)
- 2.7.3 Summary of Clinical Efficacy
- 2.7.4 Summary of Clinical Safety
5.3 Clinical Study Reports
- 5.3.5.3 Reports of Analyses of Data from More than One Study (including Any Formal Integrated Analysis, Meta Analysis and Bridging Analyses

Sections 2.7.3 and 2.7.4 should contain summarized information from the full ISE and ISS, only in unusual cases should the narrative parts of the full ISE or ISS and the summaries in sections 2.7.3 and 2.7.4 be the same.

Sections 5.3.5.3, should contain more detailed in-depth analysis, and unlike Module 2, Module 5 has no space limitations, Module 5 is the appropriate CTD / eCTD section for analyses containing large appendices of tables, figures and data sets typically found in an ISE and ISS.

More detail is provided in the Guidance and this should be reviewed before starting these sections in your CTD or eCTD.

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

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Posted in clinical, medical report, regulatory, report

Tagged CTD, drug development, eCTD, FDA, Regualtory Guidance

FDA Draft Guidance – Label Comprehension Studies for Non-prescription Drug Products

Posted on May 3, 2009 by admin| 3 Comments

It has been a busy week for new guidance and draft notices from the regulators, and this latest one is new draft guidance for Label Comprehension Studies for Non-prescription (over the counter) drug products.

The Food and Drug Administration (FDA) often requires sponsors to conduct label comprehension studies that are designed to evaluate proposed nonprescription drug product labeling. This guidance is intended to provide recommendations to industry on conducting label comprehension studies. A label comprehension study is a tool that can be used for assessing the extent to which consumers understand the information conveyed by proposed nonprescription drug product labeling and then apply this information when making hypothetical drug product use decisions.

When designing and conducting a label comprehension study it is important to:

Clearly state the purpose of the study
Identify the communication objectives (the important concepts that need to be understood by the consumer)
Enroll a demographically diverse population with varying levels of literacy
When necessary, enrich the study with subjects who have specific characteristics that are relative or absolute contradiction to the use of the drug product
Specify a study design that meets study objectives and calculate the appropriate sample size
Construct a questionnaire that targets the communication objectives
Use test labeling as close as possible to the final product label
Minimize factors that may contribute to a biased study
Compare different versions of the label to study the effect of variations in working and information location on comprehension.

Study Objectives

Primary Communication Objectives: the information that has the greatest clinical significance, target understanding should be 90% or greater. (indications, dose and dose interval, contraindications, warnings, and drug interactions, and when to stop taking the product)

Secondary Communication Objectives: Address areas of less critical importance and 80% or higher understanding is the target. (general health information)

Self Selection: the decision consumers make to use or not use a drug product based on reading the information and applying their own personal medical history.

Study Populations

The study should include all subjects who could potentially use the drug product, regardless of their age, sex, underlying medical conditions, and use of concomitant medications. The study should test label comprehension in a general population whether or not individuals express interest in using the drug product.

Label comprehension studies also should enroll a low literacy cohort. This low literate population should represent a range of low literacy below an 8th grade reading level.

Statistical Considerations and Data Analysis

The primary endpoints should be the endpoints capable of capturing the most relevant and convincing data on consumer comprehension of the critical label elements.

Based on the clearly defined primary endpoints, the study protocol should also specify what criteria determine success for the study. These success criteria should be related to the predefined target level of comprehension for the primary communication objectives.

Sample Size Considerations

The number of subjects in a label comprehension study should be large enough to provide a reliable answer to the primary communication objectives. Sizing of such a study should be based on the success criteria.

Questionnaire Design

The questionnaire design should: 1) clearly reflect the communication objectives of the study; and 2) optimize the validity and interpretability of the information collected. Wording, question structure, and question sequences significantly affect the validity and interpretability of the data collected.

Questions should assess specific objectives
Simple vocabulary should be used
Questions would be direct, specific and unambiguous
Different types of questions should be used, open, closed etc
Closed questions should be validated with open-ended probing questions (e.g. please explain your answer)
if answers are incorrect, open ended probing questions should be issued to investigate the cause of the error
Leading question should be avoided
Multiple choice should be clear and only one correct answer (include I don’t know)

Guidance is also provided on location, conduct of the study, data analysis and final reporting and interpretation.

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

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Posted in clinical, manufacturing, Uncategorized

Tagged drug guidance, FDA, Regulations, study design

The pharmaceutical industry faces unprecedented barriers to evolution

Posted on May 3, 2009 by admin| 1 Comment

I have just read an interesting article from Datamonitor and through I would share it with you:

The article argues that the pharmaceutical industry’s evolving business model in response to growing regulatory constraints has so far helped it maintain profits and growth will face some serious challenges in the near future and these challenges may overcome whatever changes the industry can come up with and impact strongly on profits. The two larges challenges are the global economic downturn and the President Obama’s planned overhaul of the US health care system.

The pharam industry’s model of “pharm 2.0″ has helped it overcome reduced R&D efficiency, increased price competition and increased generic competition, but how will the industry fair against these even larger challenges.

In the US (the worlds largest drug market) the economic downturn means that more and more people are now being left uninsured (approximately 15% of the population) and public provision will have to grow to accommodate them, but budget constraints will lead to increased pressure to abandon expensive brands in favour of generics and biosimilars, also drug reimporting will cut into markets.

Many small companies are facing a bleak future as they are unable to raise the development capital they require. How will the industry respond to these challenges, more mega mergers, a switch away from in-licensing to internal R&D as smaller companies fail to survive long enough to delivery their technologies up stream.

Its an interesting article and worth reading in full.

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

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Posted in business

Tagged Business Review, markets, pharma industry

EMEA publishes a reflection paper – Recombinant Adeno-Associated Viral Vectors

Posted on May 3, 2009 by admin| 8 Comments

The EMEA today released a reflection paper regarding Quality, non-clinical and clinical issues relating specifically to recombinant adeno-associated viral vectors. It is still open for comment until September 2009.

Recombinant adeno-associated viral (rAAV) vectors are derived from the single stranded DNA virus adeno-associated virus which belongs to the genus dependovirus within the Parvoviridae family. As the name suggests the wild type virus is incapable of independent replication and relies on co-infection of a helper virus to enable a lytic replication cycle (Gonclaves, 2005). Adenovirus (Ad), herpes simplex virus (HSV), pseudorabies virus (PrV) and human papilloma virus (HPV) are known to support wild type AAV replication.

Given the basic biology of the ‘parent’ virus, the methods for manufacture and quality control of product are complicated, and the long-term fate of the administered vector is at present unknown. There are a number of manufacturing strategies that can be used to produce rAAV vectors.

The aim of this reflection paper is to discuss quality, non-clinical and clinical issues that are specific only to the development of rAAV vectors as medicinal products. The paper goes on to discuss in some details the different manufacturing methodologies that can be used to generate rAAV including:

Virus containing production systems (helper virus & hybrid vectors)
Virus-Free production systems (tri-plasmid transfection & packaging cell lines)
Self-complementary adeno-associated virus

There are a number of quality considerations that are specific to these systems, from the standard issues of cell banking, seed stock and qualified cell lines, virus origine and stock control/testing. There are also a number of specific issues to be considered:

Virus Containing Production Systems: The main disadvantage of this system is the potential for contamination of the product with the helper/hybrid virus,and strategies for dealing with this are described. “It is recommended that a quality specification for the helper/hybrid virus is set, and the testing strategy detailed in the Ph. Eur. (Monograph 5.14 Gene Transfer Medicinal Products for Human use) can be used for guidance in defining an appropriate testing program. In particular, if the helper/hybrid virus is considered to be replication incompetent, the specification should include a test for replication-competent virus contamination.”

Virus Free Production Systems: Limitations of a manufacturing approach that relies solely on plasmid transfection lie in the difficulties of process scale up and the consistency of manufacture due to the inherent variability of the transfection process itself. However, the advantage of such an approach is that the quality of the final product is improved as there will be no contamination of the product with a helper/hybrid virus. It is recommended that the transfection conditions are thoroughly evaluated and optimized at each scale of manufacture to assure consistency in product quality and yield. Following each manufacturing change product characterization should be undertaken to assure that the introduced changes do not impact on product quality. Furthermore, the purification process should be sufficiently robust to assure removal of excess plasmid from the final product. Quality issues specific to packaging cell lines are identical for those used to manufacture recombinant proteins in that the genetic stability of construct should be shown, at or beyond the expected number of population doublings required for manufacture.

Issues of Non-Clinical Evaluation

Choice of Animal Model – AAV is a species specific virus, therefore it is possible that the biodistribution of a human serotype derived vector in a mouse or rat may not correlate to that when administered to man as cellular/organ uptake may be different as a result of differences in, or differential expression of, the receptor used for entry. A number of animal species have been used in non-clinical evaluation of rAAV vectors (rats, mice, rhesus monkey, non-human primates, dogs, cats and pigs); however it is not clear which is the most appropriate model to use, and it may be necessary for more than one species to be used to complete a full non-clinical development program. Given these difficulties there may be scientific justification for using in pivotal non-clinical studies, a serotype of virus that is specific to the animal model of choice, rather than the human serotype that will be used in clinical studies. Such studies may provide more useful information in relation to biodistribution and the impact of pre-existing immunity to the vector to it.

Vector Persistance – The safety of rAAV in terms of insertional mutagenesis is still under debate following a recent publication where an increased rate of hepatocellular carcinoma was observed in neonatal mice treated with a rAAV (Donsante, 2007). While this study is not definitive in confirming the oncogenic potential of these vectors (Kay, 2007), the implications of the study can not be ignored, and the level of integration of the vector under investigation should be evaluated. Non-clinical studies should be considered which are designed to investigate how long-term gene expression is expected to be achieved i.e. episomal or integration.

Tissue Tropism – Different serotypes of AAV have been associated with specific tissue tropisms, for example AAV 1, 6 and 7 are effective at transducing muscle cells; serotype 9 preferentially transducing the myocardium and AAV 5 is suggested to be more tropic to the airway epithelium and the central nervous system (at least in the mouse model). This preferential transduction activity does not mean however, that the vector is not distributed to other organs. It is possible therefore, that tissue tropism defined non-clinically may not be observed following administration to humans, and it is recommended that a cautious approach is taken when translating non-clinical data to humans.

Reactivation of Productive Infection – When developing rAAV vectors as medicinal products the consequence of long-term episomal maintenance and the potential for re-activation of virus if the subject is infected with both wild-type AAV and a helper virus should be considered. Where possible or relevant, this should be investigated in non-clinical studies such as those described by Afione et al (Afione, 1996). Associated treatment during clinical studies i.e. chemotherapy, immuno-suppression, anti-inflammatory medicines, may also impact on virus biodistribution and maybe even the likelihood of viral reactivation, particularly if immuno-suppression is being given. Where possible these additional treatments should be addressed during non-clinical evaluation of the product.

Germ-line transmission – Biodistribution studies have shown in the mouse and the rat that rAAV DNA can be detected in gonadal DNA (Arruda, 2001) for a variable duration. Furthermore following hepatic artery delivery of a rAAV for the treatment of hemophilia B, transient dissemination to the semen in 1 patient was observed (Schuettrumpt, 2006). The potential for germ-line transmission can not therefore be entirely ruled out (Honaramooz, 2008), as such it is recommended that germ-line transmission studies are undertaken prior to first in man studies.

Environmental risk Considerations

There is a substantial amount of literature available suggesting that shedding of rAAV is dependent on the dose and route of administration, and that vector DNA can be detected for a number of weeks in serum, and early times i.e. day 1 post administration, in saliva, serum, urine and semen (Favre, 2001; Manno, 2006; Provost, 2005). Ideally, if positive DNA signals are observed, the samples should be followed up for infectious virus quantification. The data derived from non-clinical shedding studies and from early phase clinical studies can then be used to assess the likelihood of transmission and to justify the extent of viral shedding evaluation in subsequent trials.

Clinical Considerations

Biodistribution and shedding studies – The extrapolation of biodistribution data from animal models to humans is not straight forward. It is recommended that wherever possible an investigation into the biodistribution of the vector, by screening for DNA sequences in the first instance, should be included within a clinical trial protocol is included.

Immunogenicity – Equally the extrapolation of immunogenicity data for therapeutic applications of AAV vectors from animal models to humans is not simple, and the route of administration may also impact on the immunogenic profile of the product. It is recommended therefore that consideration is given to the potential of subjects having pre-existing antibodies to the serotype of AAV under investigation, and that evaluation of the immunogenicity of both the vector and the transgene is assessed in terms of neutralizing and non-neutralizing antibody formation during clinical trials

Germ-line transmission – The question of germ-line transmission in humans has not been fully resolved and short term DNA persistence has been observed in semen (serotype 2), therefore it is recommended that germline transmission is investigated during clinical studies and that the use of barrier contraception for individuals enrolled in clinical trials is included in study protocols.

Long-term follow up – Non-clinical studies may indicate long-term persistence of the vector, be it due to viral DNA integration or episomal maintenance, in which case long-term follow-up of the patients treated with a rAAV product could be necessary, not only in terms of safety evaluation but also efficacy. It should also be considered that where these vectors are being investigated for preventive vaccination uses, long term expression of the antigenic proteins may be a safety risk rather than a desired outcome.

The paper goes into greater detail on these issues and requires detailed consideration for those working in this field.

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

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Posted in biotechnology, clinical, manufacturing, pre-clinical, regulatory

Tagged EMEA, reflection papaer, regulatory, Viral Vectors

New EMEA Draft Concept Paper – Immunogenicity Assessment of Manoclonal Antibodies for In-vivo clinical use

Posted on May 3, 2009 by admin| 1 Comment

The EMEA release for review a draft concept paper today (24th March) on immunogenicity assessment of monoclonal antibodies for in-vivo clinical use. the consultation period lasts until June 2009.

Backgound to the concept paper

Unwanted immunogenicity is a significant problem with therapeutic biologicals. The clinical problems associated with unwanted immunogenicity vary in nature and incidence. The importance of the unwanted immunogenicity problem has led to the preparation and adoption of the ‘Guideline on Immunogenicity Assessment of Biotechnology-Derived Therapeutic Proteins’ by the CHMP (adopted April 2008).
Monoclonal Antibodies (mAbs) comprise a large important class of therapeutic biologicals. Different mAb products share some properties, but may differ in other aspects. Many mAb products are known to be associated with unwanted immunogenicity. Some issues pertaining to unwanted immunogenicity of mAbs differ in important aspects from those generally associated with therapeutic biologicals.

The Main problem being addressed

The incidence of immunogenicity associated with mAbs differs greatly between products, patients and even in different studies with the same product and patient type. The complexity of structure of mAbs possibly explains at least some of this variation. In some cases, especially with humanised or human sequence mAbs the immune response is predominantly anti-idiotypic, which clearly can compromise clinical responses to the mAb. In some cases the induced antibodies reduce clinical responses to the mAb to such an extent that further therapy has to be terminated.
The very large number of mAbs in clinical development and undergoing regulatory scrutiny emphasises the critical need for provision of appropriate guidance on the unwanted immunogenicity of this large class of biologicals. Questions on immunogenicity are often asked during assessments of marketing authorizations for mAbs. The development of biosimilar mAbs is prevalent in various parts of the world, which again stresses the importance of having good guidance available, as unwanted immunogenicity is well known to also be a concern with biosimilars.

The main recommendation from this concept paper are, the drafting of a guideline on immunogenicity assessments of monoclonal antibodies intended for in vivo clinical use. The EMEA are looking for expert input and opinion into this subject from the pharmaceutical industry.

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

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Posted in biotechnology, clinical, pre-clinical, regulatory

Tagged biotechnology, biotechnology development consultant, draft, EMEA, Guidlines, monoclonal antibodies, regulatory

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Monthly Archives: May 2009

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EU announces 246 million Euros of medical research funding and tells us what they are looking for in the next round

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EMEA puts out a new concept paper – developing a guidline for the use of Pharmcogenomic Methodologies in the Pharmacokinetic Evaluation of Medicinal Products

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Pause in Normal Service

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The pharmaceutical industry faces unprecedented barriers to evolution

EMEA publishes a reflection paper – Recombinant Adeno-Associated Viral Vectors

New EMEA Draft Concept Paper – Immunogenicity Assessment of Manoclonal Antibodies for In-vivo clinical use

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