Tag Archives: regualtory

PhRMA Issues Revised Principles on Conduct of Clinical Trials and Communication of Clinical Trial Results

Posted on April 27, 2009 by admin| 2 Comments

On April the 20th the Pharmaceutical Research and Manufactures of America (PhRMA) issued a revised “Principles on Conduct of Clinical Trials and Communication of Clinical Trial Results” – These guidelines outlines a number of elements including: Principles on the conduct of clinical research, registration of clinical trials and disclosure of study result summaries. Some of the more important changes include:

Registration of Clinical Trials – PhRMA advises member companies to register on a public database timely summary information about all clinical trials that study products in patients.  PhRMA defines timely as 21 days of enrollment of the first patient in the clinical trial. (this includes phase 1 studies), the PhRMA guidance is more stringent and goes further than FDA rules.

Submission of Summary Results - As it did in its prior version, PhRMA promises to disclose summary results of all clinical trials for approved drugs, regardless of the study’s outcome.  In a major change from its prior version, however, PhRMA also promises to post timely summary results of all clinical trials if the sponsor discontinues development of the drug.  PhRMA defines timely as 12 months after the trial ends, 30 days within drug approval or a year after a company discontinues the drug development program.

Disclosure of Conflict of Interest in Articles - The revision urges sponsors to encourage physicians and researchers to disclose conflict of interest information when authoring manuscripts to medical journals.  Authors that submit a manuscript to a medical journal, according to PhRMA, should disclose “all financial and personal relationships that might bias their work,” and explicitly state whether potential conflicts exist.

Increased Qualifications Needed for Authorship – The revised Principles would make it more difficult to be listed as an author of an article in a medical journal.  These more stringent guidelines adhere to the standards of the International Committee of Medical Journal Editors.

Provision of Study Results to Investigators and Participating Patients – PhRMA directs sponsors to provide all investigators with a full summary of the study results even if an investigator does not contribute to the publication of the study.

Sponsors Right To Review – PhRMA also confirms that sponsors have the right to review manuscripts, presentations, or abstracts that result from the sponsor’s studies or use the sponsor’s data prior to publication or presentation.

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  evelopment 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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New FDA Draft Guidance – Non Clinical evaluation for Anticancer Pharmaceuticals

Posted on April 2, 2009 by admin| 1 Comment

The FDA has produced some draft guidance aimed at establishing an internationally accepted objectives and / or recommendations on the design and conduct of nonclinical studies to support the development of anticancer pharmaceuticals in patients with advanced disease and limited therapeutic options.

Because malignant tumours are life-threatening, the death rate from these diseases is high, and existing therapies have limited effectiveness, it is desired to provide new effective anticancer drugs to patients more expeditiously. Nonclinical evaluations are intended to 1)identify the pharmacological properties of a pharmaceutical, 2) establish a safe initial dose and 3) understand the toxicological profile.

These new guidlines only apply to pharmaceuticals intended to treat cancer in patients with late stage or advanced disease regardless of the route of administration, including both small molecule and biotechnology-derived pharmaceuticals.

Studies to support nonclinical evaluation

Pharmacology – prior to phase I studies, preliminary characterization of the mechanism(s) of action, resistance, and schedule dependencies as well as anti-tumour activity should have been made. appropriate models should be selected based on the target and mechanism of action but need not be studied using the same tumour types intended for clinical evaluation. these studies can provide proof of principle, guide schedules and dose escalation schemes, provide information for selected test species, and aid starting dose selection.

Safety Pharmacology – as assessment of vital organ function should be available before initiation of clinical studies. Stand alone safety pharmacology studies need not be conducted to support studies in pateiutne with late stage cancer or advanced disease.

Pharmacokinetics – the evaluation of limited kinetic parameters, e.g. peak plasma levels, AUC and half life in the animal species used for non-clinical studies can facilitate dose escalation during phase I.

General Toxicology – The primary objective of Phase I clinical trials in patients with cancer is to assess the safety of the pharmaceutical. This can include dosing to a maximum tolerated dose (MTD) and dose limiting toxicity (DLT). Therefore, determination of a no observed adverse effect level (NOAEL) or no effect level (NOEL) in the toxicology studies is not considered essential to support clinical use of an anticancer pharmaceutical. To support Phase I clinical trials at least one nonclinical study should incorporate a recovery period at the end of the study to assess for reversibility of toxicity findings or the potential that toxicity continues to progress after cessation of drug treatment. Toxicokinetic evaluation should be conducted as appropriate.

Reproduction Toxicology – These studies are not considered essential to support clinical trials intended for the treatment of patients with late stage or advanced cancer. These studies are also not considered essential for pharmaceuticals which target rapidly dividing cells in general toxicity studies or belong to a class which has been well characterized in causing developmental toxicity. Generally no fertility study is warranted to support the treatment of patients with late stage or advanced cancer. A peri- and postnatal toxicology study is generally not warranted to support the treatment of patients with late stage or advanced cancer.

Genotoxicity – Genotoxicity studies are not considered essential to support clinical trials for therapeutics intended to treat patients with late stage or advanced cancer.

Immunotoxcity – For anticancer pharmaceuticals the design components of the general toxicology studies are considered sufficient to evaluate immunotoxic potential and support marketing.

The guidelines go on to describe how you can use the pre-clinical data in designing you clinical trial: start dose for first administration in man, dose escalation and the highest dose in clinical trials. the guidelines also provide guidance on duration and schedule of toxicology studies to support initial clinical trials, the duration of toxicology studies to support continued clinical development and marketing, how to manage combination pharmaceuticals and Finlay the non clinical studies to support trials in pediatric populations. Other considerations addressed in the guidelines include conjugated agents, liposomal products, evaluation of drug metabolites, and evaluation of impurities.

Table – Example schedules for anticancer pharmaceuticals to support initial clinical trials. (reproduced from FDA guidelines S9)

moz screenshot 1 New FDA Draft Guidance Non Clinical evaluation for Anticancer Pharmaceuticals

table1 300x182 New FDA Draft Guidance Non Clinical evaluation for Anticancer Pharmaceuticals

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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eCTD (electronic Common Technical Document)

Posted on February 20, 2009 by admin| 2 Comments

As part of our consulting work in drug development we frequently get involved in the production of Regulatory Documentation, often directing and managing the process. Regulators are now preferring the use eCTD format, this is a trend that will only get more important as time goes on and people developing drugs will need to start to think and implement these process if they are not already doing so. It is a global movement in 2000 the ICH agreed a eCTD format that is being taken up globally, in Europe it is set to become mandatory in 2010 with the USA and Canada following shortly after.

The number of eCTD applications being submitted is on the increase, there has been a 300% increase between Dec 2007 and Dec 2008, unfortunately however this is coming at a cost and that is in terms of errors being made. But the majority of these errors can be avoided, through good planning and QC processes.

Basics of eCTD:

The eCTD is built using specialist software, the output follows the module format we are familiar with, but the document uses an XML backbone to generate and maintain a table of contents (TOC), this TOC is bookmarked and hyperlinked so the reader can navigate and move through the document with ease.

Benefits of eCTD

Less physical storage space than conventional paper documents (less money on space and security)

Less time to move and update (again massive cost savings to be made)

Hugely efficient for review bodies to deal with (speeded up review times and reduce errors)

The status of the document can be easily monitored (money savings, time savings, and error reduction)

Global re-formatting is fast and simple (reduced and cost and time)

Current Status

There has been a huge rise in the number of eCTD’s being submitted, however with anything new there have been a large number of errors, most likely broken hyperlinks and failing TOC’s. The regulatory authorities have turned a blind eye to these errors as the other benefits have easily overcome these and the process is still new to so many. However this period of grace appears to be running out.

“its been 6 months since the CDER division of the FDA started requiring all electronic submissions to use the eCTD format, and all is not well” – Ann Neuer, The eCTD a six month checkup, BioIT-World 28th July 2008

How to avoid errors

  • Early planning and preparation
  • Appreciation of regulatory requirements
  • Understanding of the appropriate regulatory guidance
  • Knowledge of eCTD format and content
  • Knowledge of the country specific eCTD requirements
  • Knowledge of the eCTD e-submission processes
  • Utilising the appropriate tools
  • Consistent attention to detail
  • QC / QA processes in place before you start
  • You need to publish regularly to ensure problems are not arising.

Guidance Documents

there are a number of guidance documents available for review.

EMEA -http://esubmission.emea.europa.eu/doc/index.html

FDA – http://www.fda.gov/cder/regulatory/ersr/default.htm

Canada -http://www.hc-sc.gc.ca/dhp-mps/prodpharma/applic-demande/guide-ld/ctd/ectd/draft_ebauche_prep_ectd_format_rev-eng.php

It is important that you check these sites regularly to ensure you are up to date with requirements.

Good Practice

There are a number of processes and tools that can be highly effective in maintaining a eCTD project.

  • QC often and early – cheack all hyperlinks and TOC to ensure they are working well
  • Ensure all people involved are using the same software version and they are kept up to date
  • Legacy documents need to be converted into a searchable format, scan with OCR or re-type
  • Use the online submission tools for regulatory bodies

As consultants working in the area of drug development, regulatory strategy and development strategy we are often involved in these kinds of document development processes and good housekeeping is vital. eCTD is coming to us all so its best we get up to speed as early as possible.

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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Conditional Approval – An important short cut to the market

Posted on January 6, 2009 by admin| Leave a comment

The EMEA (European Medicines Agency) can recommend a product is given Conditional Approval, the CHMP (Committee for Medicinal Products for Human Use) bases a positive opinion on the data available. Usually this data is not sufficient to award a full approval, but is of such a positive nature and the drug of such obvious benefit to a group with high unmet medical need that they will allow it to go to market whilst the clinical data is strengthened.

The FDA has a similar approval process.

The CHMP make this recommendation on the understanding that the company will undertake an agreed programme of works aimed at strengthening the data package. The company are under an obligation to fulfill this programme of work. In order to ensure that they do the conditional approval is reviewed annually until full approval is granted.

This can be an important regulatory avenue for companies that have relatively well known drugs that are being targeted at a new indication, as long as there is considerable unmet medical need, and very strong indication of safety, and a good indication of ethicacy. Because you can in effect go to market after phase 2, and the revenues raised can help fund your phase 3 programme, it can accelerate your development and maintain your equity standing.

If conditional approaval in pursued in an orphan indication you could be in the market place with a very limited number of patients and perhaps a single clinical trial.

During our work as development consultants we have pursued this path for clients and it is an effective tool for maximising the outcomes of R&D spending but also improtant in ensuring patients with a despirate need for drugs can get access as quickly as possible.

If you would like to know more about this please feel free to get in touch.

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 using the contact form or email Damien at damien.bove@idaconsultants.com

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