Tag Archives: regulatory

EMA Announce Meeting on Paedatic Regulation in its 5th Year

Posted on September 10, 2011 by admin| Leave a comment

EMA Announce Meeting on Paediatric Regulation in its 5th Year

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Conference objectives include updating participants how to deal with paediatric regulatory requirements, scientific and operational challenges; exchanging experiences with regulatory authorities, academia and industry; and discussing visions, daily challenges and potential ways to move forward and further improve processes for paediatric drug development.

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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 Consultation on Its Road Map to 2015

Posted on March 10, 2010 by admin| Leave a comment

Drug Regulators, EMA (EMEA), Publish Consultation on Its Road Map to 2015.

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The European Medicines Agency has launched a three-month public consultation on its Road Map to 2015, coinciding with its 15th anniversary on 26 January 2010
European and international partners, stakeholders, including patients’ and doctors’ organisations as well as pharmaceutical industry, and the public are invited to make their views known on the Agency’s future strategic vision, set out in the document ‘The European Medicines Agency Road Map to 2015: The Agency’s contribution to Science, Medicines, Health’. Comments should be sent using the Agency’s comments form by 30 April 2010 to mailto:roadmap@ema.europa.eu.

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Post Markeing Clinical Trials Planning – Imprelentation of the FDA section 505(o) – Draft Guidance

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

Drug Regulatory FDA publishes draft guidance for comments on Section 505(o) – Post marketing Clinical Trials

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:

Subpart H and subpart E accelerated approvals for products approved under 505(b) of the Act or section 351 of the PHS Act, respectively, which require postmarketing studies to demonstrate clinical benefit (21 CFR 314.510 and 601.41);
Deferred pediatric studies, where studies are required under the Pediatric Research Equity Act (PREA) (21 CFR 314.55(b) and 601.27(b)); and
Animal Efficacy Rule approvals, where studies to demonstrate safety and efficacy in humans are required at the time of use (21 CFR 314.610(b)(1) and 601.91(b)(1)).

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.

New FDAAA Authority and Requirements

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:

a timetable for completion
periodic reports on the status of the study, including whether any difficulties in completing the study have been encountered, whether enrollment has begun, the number of participants enrolled, the expected completion date.

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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This guideline ap

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

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Posted in clinical, regulatory, Uncategorized

Tagged 505(o), FDA, FDAAA, PMR, post marketing requirements, regulatory

IDA consultants Provides Regulatory Roadmap

Posted on June 8, 2009 by admin| Leave a comment

IDA consultats has been approached to provide a couple of slides that outline a regulatory roadmap, I thought I woudl share them with my readers as well, along with the notes that I provided to the speaker, I hope you find them helpful.

slide1 IDA consultants Provides Regulatory Roadmap

slide2 IDA consultants Provides Regulatory Roadmap

The pathway through MHRA/EMEA drug approval process

Speaker notes for slides

The first step is to put together your development plan, in the first instance you will require clinical trials outlines nonclinical outlines nonclinical safety outlines and GMP manufacturing plans. It is advised that you seek scientific advice at this stage unless your program is very much a vanilla program. This process of gaining a regulatory rubberstamp can prove very valuable in terms of de-risking your project and make you more attractive to investors.

In order to get your clinical trial program approved there are two routes that you can take:

There is a central review process that is run by a subcommittee of the EMEA, where you can submit your development plan and clinical trials protocols for central review this is not an approval process, it enables European wide feedback and comments upon your plans. It is voluntary for most programs however it is mandatory for biotech products and high-tech products for multinational phase 3 programs . You still need to apply for local approval after this and local ethics approval however it gives you an opportunity to countries that have a positive opinion about your program.

Most companies chose to go down the national procedure route, in which you have your clinical trial approved by the appropriate authorities in the UK this is the MHRA, you will then require local ethics approval, we advise you apply for both your CTA and your local ethics simultaneously in order to save time.

If your product is a high risk product such as monoclonal or similar, you will require an extra stage of approval by the EAG this will come before your standard CTA approval program.

You can then initiate your clinical trials programme.

For the scientific meetings and advice you will need a regulatory briefing book, this should be ideally no more than 20 to 50 pages 20 pages of the new programs 50 pages the programs are gone through a number of clinical trials, this should be very brief and to the point.

To start your official CTA process you will require full protocols, full case report forms, and a much more detailed briefing book.

In order to undertake your clinical trial you will require a CRO to manage it, it is recommended that you undergo a CRO selection process at a very early stage, you will require insurance, again the cost of insurance can be much reduced if you speak to your insurance company at a very early stage. You will require ongoing Pharmacovigilance cover, in most of the world pre-clinical and clinical trials programmes will require GMP clinical trial stock however there are a number of countries were full GMP is not required and “in the spirit of GMP” may be acceptable. This includes the USA Belgium and Holland.

I would recommend that you seek regulatory scientific advice between each of your clinical trials in order to establish that the results seen have not impacted on the regulatory acceptance of the overall design. This is probably not required if your results are exactly as you have predicted they would be.

Second slide

Once you have completed your development programme will require a product licence to sell your product in Europe. There are many routes for this: there is a central process run by the EMEA, a national process, the national process followed by mutual recognition, and decentralised process for products that are already on the market in the country.

There are many factors that go into the choice of routes to many to be discussed here. Whichever route you decide upon it is well advised to seek meetings with the regulators well before submission of your application in order to confirm acceptance of your planned route.

With the central process your application is made to the EMEA who then have it reviewed by two representative national bodies, if this is acceptable then Central European approval is granted and your product can be sold anywhere within the union.

In the national process you gain national approval with the body of your choice then you can sell your product in that country. At this point you can start a mutual recognition process where you use your existing approval to springboard approval into other selected states.

The decentralised procedure is the products are being on the market and have a market history in one or more European states, you can then proceed to gain regulatory approval in national states based upon that national approval.

Whichever route you take your require a common technical document or a an eCTD as they are known, this will ensure that your documentation is in a state that is acceptable in all this national states and also in the USA.

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

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EMEA publishes concept paper on the development of guidlines on the use of Pharmacogenomic Methodogologies in PK evaluation

Posted on June 4, 2009 by admin| 1 Comment

The EMEA has published concept paper on the development of the guidelines on the use of pharmacodynamic methodologies in the pharmacokinetic evaluation of medicinal products. In recent years there has been a rapid development regarding our understanding of the genetics behind interindividual differences in drug response. This development encompasses the area of pharmacodynamics where individual variability in genes encoding drug transporters, and drug metabolising enzymes affects the systemic and target organ exposure as as well as the occurrance of adverse drug reactions to pharmacologically active substances.

A reflection paper on the use of pharmacokinetics in the pharmacokinetic evaluation of medicinal products was published by the EMEA in May 2007. Since the drafting of this reflection paper, progress in the field has been considerable. In the light of evolution and broad acceptance of genotyping methods, as well is increased experience in the use of such pharmacognomic methodologies during drug development, it was considered appropriate to update aline this progress in the guidance on the topic.

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

The main additional topics to be addressed in the proposed guideline as compared to reflection paper are:

Clarifications regarding how and when to apply genotype during clinical development.
Data needed for evaluating the clinical relevance of pharmacogenetic effect on drug exposure as well as the benefits of applying genotyping during clinical use.
Recommendations regarding pharmacokinetic studies investigating the effect of polymorphisms at transport level.
Guidance on specific technical aspects to be considered in accessing clinically relevant polymorphism (e.g. impact of different allelic variants).

Timetable for drawing up this guidance is as follows; it is anticipated that the guidance will be available nine months after adoption of this concept paper on purely six months external consultation, before finalisation within six months. External consultation from the pharmaceutical industry and academics and professional networks is welcomed by the EMEA.

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

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Tagged concept paper, Consultancy, drug development, EMEA, pharmacogenomic, pharmacokinetic, regulatory, regulatory guidlines

EMEA Guidlines on Clinical Investigation of Medicinal Products for The Treatment of Ankylosing Spondylitis.

Posted on June 1, 2009 by admin| Leave a comment

The EMEA has published guidance on the clinical evaluation of new medical products the treatment and ankylosing spondylitis (AS), a chronic inflammatory disease that affects primarily sacroiliac joints and the axial skeleton. The prevalence has been estimated at between 0.1 and 1.1% of the population.

The guidance describes the patient characteristics/selection criteria that should be considered for inclusion of patients into clinical trials. This is of particular importance in order to establish the correct diagnosis, distinguish patients with AS from those suffering from other subtypes of spondyloarthritis, and appropriately assess the severity and extent of the disease at baseline.

The different domains to assess efficacy and medicinal product are described as well is the therapeutic claims that are distinguished from the regulatory perspective:

improvement of symptoms and signs such as pain and stiffness or enthesopathy
improvement of physical function
slowing or prevention of structural damage
prevention of disability

The guidance, furthermore, outlines strategies for early studies in man (does response trials) as well as therapeutic complimentary trials including acceptable primary and secondary endpoints to assess efficacy. Specific aspects of evaluation of clinical safety are also highlighted, specifically a need for long-term safety data in the treatment of this chronic disease.

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

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Tagged Ankylosing spondylitis, AS, Clinial Guidance, EMEA, regulatory

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

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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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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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Tagged clinical, Efficacy, EMEA, HCV, regulatory

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

FDA go Mystery Shopping

Posted on April 15, 2009 by admin| 1 Comment

Institutional Review Boards are charged with monitoring clinical trials that go through the institution to ensure patients safety and to ensure the principles for good clinical research are maintained. The FDA has decide to monitor the quality of the decisions being made by some IRB’s in commercial research institutes, in what appears to be a break from the normal methods of Audit, where they review past decisions, in the case of Coast, a for profit Independent review board, the FDA submitted a bogus clinical trial protocol, for a fictitious product and fictitious company, when the board approved the study the FDA sprang its trap. Now Coast are facing some very difficult questions, shedding staff and shedding business.

Mystery shopper is a different path but this author asks where will they take it next, fake safety reports, fake adverse event reports, its the natural evolution of the Audit.

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 FDA, IRB, regulatory, Sudit

Priority Review Vouchers – and there off

Posted on April 9, 2009 by admin| Leave a comment

Some time ago we published an article about Priority Review Vouchers and how they could potentially be worth US$300million, although I have just read an estimate of US$50 to US$500 million. Well it has started now watch this space,Yesterday the FDA announced the approval of Norvartis’ combination drug product Coartem (artemether, lumefanterine) for the treatment of acute uncomplicated malaria infections in adults and children weighing at least five kilograms, and the FDA has awarded them a priority review voucher. It remains to be seen if they sell it on, for the estimated millions, or use it to speed up their own products.

For those of you who don’t know about these vouchers, how they work is if you develop a new drug against certain tropical diseases (there is a list available) the FDA gives you a voucher that can be used to grant an accelerated approval process to any product, a voucher that can be sold on. Because these vouchers if applied to a potential block buster can bring forward your access to market by at least 4 months, combined with shorter remaining patent lives on new drugs leaving development, they are expected to be worth many millions of dollars, as mentioned above values of US$500 million are being banded about.

This is obviously quite disruptive to business strategy, it could be possible to take a drug all the way to registration in a rare tropical disease with grants and charity contributions, reducing the amount needed to be raised and boosting your remaining equity well beyond what would normally be expected, then get your voucher, sell it for the many millions to fund your programmes in western disease. Its a strategy that will add significant time to your development programme but you will be sitting on the equity but its a strategy to be considered and there are many 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 clinical, regulatory

Tagged FDA, priority review vouchers, regulatory, tropical diseases

Pediatric Exclusivity After Product Approval; FDA Interpriations About Which You Might Not Be Aware

Posted on April 8, 2009 by admin| 2 Comments

This is a very interesting article that raises some good points well worthy of consideration published on FDA Law Blog run by Hyman, Phelps & McNamara, In summary the FDA grants an additional period of exclusivity for a licensed product for a period of 6 months, if the sponsor submits requested information relating to the use of the active moiety in the paediatric population. There are a number of rules and regulations involved in obtaining this exclusivity (perhaps a full article on this subject is justified – I will try and get one in this week). However what this interesting article points out is that the FDA’s interpretation of the benefits goes beyond what you may think and their points of view are justified with case studies.

FDA statement

“Pediatric exclusivity will attach to exclusivity and patent protection listed in the Orange Book for any drug product containing the same active moiety as the drug studied and for which the party submitting the studies holds the approved new drug application (505A(a) and (c)). For studies conducted on an unapproved drug, pediatric exclusivity will also attach to any exclusivity or patent protection that will be listed in the Orange Book upon approval of that unapproved drug. FDA will attach pediatric exclusivity to protections listed at any time for a drug product as approved at the time pediatric exclusivity is obtained, as described further in section X.C.”

FDA statement

“Previously earned pediatric exclusivity will not apply to new patents or exclusivity covering later-filed applications or supplements containing the same active moiety for which a sponsor previously earned pediatric exclusivity, unless the data that earned the prior pediatric exclusivity is essential to approval of the new application or supplement.”

Interesting interpretation:

When the FDA issues a Paediatric Written Request (PWR) for a drug product that is a racemic mixture, any pediatric exclusivity granted as a result of that PWR applies not only to the to the racemic mixture but also to the sponsors other products containing either enantiomer whether or not FDA’s PWR specifically identifies each enantiomer in the racemic mixture.

previously earned pediatric exclusivity can apply to certain new Orange Book-listed patents if those patents relate back to the drug product when pediatric exclusivity was granted.

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 Data Exclusitity, exclusivity, FDA, paediatric, pedatric, regulatory

Inclusion of Women of Child Bearing Potential- new ICH guidance

Posted on March 30, 2009 by admin| 1 Comment

There has been a major revision of the ICH guidance regarding the use of women of child bearing potential in clinical trials.

“In all ICH regions, inclusion of women of childbearing potential in clinical trials may be acceptable without non-clinical reproductive/development toxicology studies in certain circumstances”

The current ICH M3 states:

In the EU, assessment of embryo-fetal development should be completed prior to Phase I trials in women of childbearing potential.

In the US women of childbearing potential may be included in early, carefully monitored studies without reproduction toxicity studies provided appropriate precautions are taken to minimise risk.

The revise M3 states:

in all ICH regions women of child bearing potential can be included in clinical trials without non-clinical development toxicity studies (e.g., embryo-fetal studies) in certain circumstances.

In all ICH regions, women of child bearing potential can be included in repeated-dose Phase 1 and 2 trials prior to the conduct of the female fertility study since an evaluation of the female reproductive organs is performed in the repeated dose toxicity studies.

Two forms of contraception are required, one barrier and one hormonal.

Please note that in the EU this is NOT default position, it only applied in certain cases and includes restriction on numbers and duration.

This is important for a regulatory strategy and clinical development strategy front as it can have a huge impact on trial designs, and more importantly recruitment rates in early development. it also reduces the early stage burden in the development of female specific therapies.

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 ICH M3, regulatory, regulatory guidance, WOCBP

Neglected Diseases – FDA Review Vouchers – a new source of revenue

Posted on January 26, 2009 by admin| 3 Comments

In September 2008 the FDA launched a new federal programme designed to increase the amount of work being undertaken in certain neglected tropical infectious diseases. (implemented by the FDA amendments act of 2007). This programme will award a sponsor of a drug for a tropical disease a voucher entitling the company an expedited review for any other drug application. The expedited review can reduce the time for a review from 18 to 6 months saving upwards of a year, which can add extra time on market giving some additional $300million plus in additional sales.

Whilst most small companies developing drugs in Tropical Diseases would be unlikely be in a position to take full advantage of these vouchers and access there full potential value, the regulations allows the original sponsor company to sell this voucher to another company. This is the real trick to these regulations. This voucher represents a significant asset, to be exploited and can be a critical element of your licensing negotiations with larger companies once you have developed your product, and these neglected tropical diseases are likely to be considered orphan in the USA so reduced development programmes and speedier registration are likley ot be obtainable.

On its own its impact is interesting but when combined with other regulatory pathways it can be a powerful way of building value quickly into your product, fast tracking you to approval, generating an valuable asset and getting your technology ready for a mainstream registration via a licensing deal with a larger pharmaceutical company.

We have looked at these regulatory strategies as part of our work as drug development consultants. If you want to know more don’t hesitate to get in touch using the contact form or email Damien at damien.bove@idaconsultants.com

Damien Bové works as a drug development consultant (pharmaceutical or biotechnology), we work with our clients to define a development target, define a 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 regulatory

Tagged FDA, Neglected disease, regulatory

Data Exclusivity Extends Market Protection to 11 years without a patent being required

Posted on January 19, 2009 by admin| 1 Comment

Data exclusivity is an important tool in the area of pharmaceuticals and biological therapies, when you successfully apply for a product license in many European countries. This period of data exclusivity was originally implemented to cover areas where patent protection was limited. When a generic application is made for an existing drug, the pre-clinical and clinical work is not repeated instead the generic applicant references the existing products regulatory filing which the authorities hold. Data exclusivity means that for the period the regulatory authorities will not allow your data to be used for generic applications. This does not guarantee market exclusivity but it does increase the work load and expense required from a generic manufacture who is seeking to launch a product. Data exclusivity last for 8 years in the majority of European countries, then there is an additional 2 years of market exclusivity after this point, during which generic applications can be filed and considered but no licenses will be awarded until the period ends this allows a 10 year market exclusivity. Another important note is that if a new indication is filed in the first 8 years an additional year of data exclusivity can be added on brining total protection up to 11 years. This extra year can also be applied if the product successfully switches from Prescription only to Over the Counter.

This can be a great tool if your seeking a new indication for an existing generic drug, or if your development has taken a long time which has resulted in only a short time left on your patent when you complete your licensing applications.

If you want to know more don’t hesitate to get in touch using the contact form or email Damien at damien.bove@idaconsultants.com

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Posted in regulatory

Tagged Data Exclusitity, Drug, EMEA, regulatory

New FDA review rules, new EMEA & FDA paediatric rules and new EMEA safety rules are going to torpedo your development project and knock a large amount of the value out for your IP if your not ready!

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

We have the course that will ensure your well prepared, and at only £500 its great value.

Click Here for Course Details

FDA: At the end of 2007, the USA government announced a wide ranging and disruptive review of the FDA mandate. It affects most element of what the FDA do and consequently what is required of the drug development industry. These new rules are now in force and companies need to be ready to deal with it. If your not doing the right things at Proof of Concept stage you might find your not ready to go into man when you think you are, its going to impact the value of your IP and your credibility to investors.

Paediatric: the FDA and EMEA have put in place some tough new rules governing the area of Paediatric clinical trials (Its not just for paediatric drugs these rules will impact every programme). You have to have a plan for paediatric plan, and in the near future you will need to have started the implementation of that plan before they will consider your technology for approval. If your not ready and have not considered these things your going to wast time and reduce the value of your IP. As you go into man, this is when you need to start considering these things.

EUCTD: We all think we know how the Clinical Trials Directive was going to impact, but now that we have been living with these rules for some time now we can now see the reality of these rules and the exceptions that have been thrown up. You need to make sure your all over these rules as it will impact your future development.

We are running a course in February that will assist you tackle these issues are come out smelling of roses.

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Posted in regulatory

Tagged Consultancy, Course, EMEA, FDA, regulatory

Orphan Drugs – FDA/EMEA single application process

Posted on September 29, 2008 by admin| Leave a comment

Many of you will know about orphan drugs and the assistance available from the regulatory bodies should you be awarded an orphan registration.

Applying for orphan registration is a straight forward process, however there are ways of making it even more simple. The FDA and EMEA have combined their application processes into a single form, so it is now possible to fill in a single form and submit it to both regulators.

It is possible to get twice the return for your orphan application effort. But why would you want to do this you may ask what is the benefit? There are a number of commercial benefits from obtaining an orphan registration:

scientific assistance (get your development plan rubber stamped)
easy development requirements (more attractive to investors)
a chance to get some much needed publicity
demonstrates your team have the capability to deliver in the drug development environment.

if you have any questions about orphan registration then just drop me an e-mail, damien.bove@idaconsultants.com and I will be sure to help.

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Posted in regulatory

Tagged EMEA, FDA, Orphan, regulatory

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EMA Announce Meeting on Paedatic Regulation in its 5th Year

EMA Announce Meeting on Paediatric Regulation in its 5th Year

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Drug Regulators, EMA (EMEA), Publish Consultation on Its Road Map to 2015

Drug Regulators, EMA (EMEA), Publish Consultation on Its Road Map to 2015.

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Avoid Expensive Mistakes, Keep On Top of New and Changing Regulations for Free!

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Drug Regulatory FDA publishes draft guidance for comments on Section 505(o) – Post marketing Clinical Trials

New FDAAA Authority and Requirements

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EMEA publishes concept paper on the development of guidlines on the use of Pharmacogenomic Methodogologies in PK evaluation

EMEA Guidlines on Clinical Investigation of Medicinal Products for The Treatment of Ankylosing Spondylitis.

EMEA re-posts Points to Consider on Missing Data

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

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

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

FDA go Mystery Shopping

Priority Review Vouchers – and there off

Pediatric Exclusivity After Product Approval; FDA Interpriations About Which You Might Not Be Aware

Inclusion of Women of Child Bearing Potential- new ICH guidance

Neglected Diseases – FDA Review Vouchers – a new source of revenue

Data Exclusivity Extends Market Protection to 11 years without a patent being required

New FDA review rules, new EMEA & FDA paediatric rules and new EMEA safety rules are going to torpedo your development project and knock a large amount of the value out for your IP if your not ready!

Orphan Drugs – FDA/EMEA single application process

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