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Uncategorized | BioQuality.biz

Coming soon!

Coming Soon!

Flurry of Papers Published on Unwanted Immunogenicity

Unwanted immunogenicity is a significant problem for many biopharmaceuticals, and its detection is crucial for development, approval, and successful commercialization of these products. Several papers have been published recently on this important topic. Following are brief synopses of two of these papers. For references to 10 more recent publications, see our upcoming April-May issue.

Preclinical Models Used for Immunogenicity Prediction of Therapeutic Proteins.
Brinks V, Weinbuch D, Baker M, Dean Y, Stas P, Kostense S, Rup B, Jiskoot W.  Department of Pharmaceutics Utrecht Institute for Pharmaceutical Sciences (UIPS), Utrecht University, Universiteitsweg 99, 3584 CG, Utrecht, The Netherlands.  Pharm Res. 2013 May 7. [Epub ahead of print]

All therapeutic proteins are potentially immunogenic. Antibodies formed against these drugs can decrease efficacy, leading to drastically increased therapeutic costs and in rare cases to serious and sometimes life threatening side-effects. Many efforts are therefore undertaken to develop therapeutic proteins with minimal immunogenicity. For this, immunogenicity prediction of candidate drugs during early drug development is essential. Several in silico, in vitro and in vivo models are used to predict immunogenicity of drug leads, to modify potentially immunogenic properties and to continue development of drug candidates with expected low immunogenicity. Despite the extensive use of these predictive models, their actual predictive value varies. Important reasons for this uncertainty are the limited/insufficient knowledge on the immune mechanisms underlying immunogenicity of therapeutic proteins, the fact that different predictive models explore different components of the immune system and the lack of an integrated clinical validation. In this review, we discuss the predictive models in use, summarize aspects of immunogenicity that these models predict and explore the merits and the limitations of each of the models.

Impact of Anti-Drug Antibodies in Preclinical Pharmacokinetic Assessment.
Thway TM, Magana I, Bautista A, Jawa V, Gu W, Ma M. Department of Pharmacokinetic and Drug Metabolism, Amgen Inc., One Amgen Center Drive, Thousand Oaks, California, 91320, USA.  AAPS J. 2013 May 8. [Epub ahead of print]

The administration of human biotherapeutics is often associated with a higher incidence of immunogenicity in preclinical species. The presence of anti-drug antibodies (ADAs) in the test samples can affect the accurate measurement of therapeutic protein (TP) in bioanalytical methods designed to support pharmacokinetic (PK) and toxicokinetic (TK) assessments. The impact can vary depending on the bioanalytical method platform and study dosing design. The goal of this study is to evaluate the impact of ADA response on the bioanalytical methods in support of PK/TK and the associated study data interpretation. Sprague Dawley rats were administered with four weekly doses of 50 mg/kg TP, a humanized monoclonal antibody. The TP in serum samples was measured using three bioanalytical methods that quantified bound and/or unbound TP to ADA. The ADA response in the animals was classified into negative, low, medium, and high based on the magnitude of the response. The presence of ADA in samples led to discrepant TP measurements between the methods, especially at time points where the TP concentrations were low. This could be due to ADA interference to the accurate measurement of ADA-bound TP concentrations. The TP concentration at last time point (C last) was reduced by 82.8%, 98.6%, and 99.8%, respectively, for samples containing low, medium, and high levels of ADA. The interfering effects of the ADA on bioanalytical methods and exposure were evident as early as 2 weeks post-dosing. This modeling approach can provide the better understanding of ADA impact on PK exposure in multiple doses.

Vaccine pills coming soon?

Vaccine Pills would be real shot in the arm for vaccine industry 😉

[click the Title above to see this entire post]

Effect of protein release rates from tablet formulations on the immune response after sublingual immunization

Borde A, Ekman A, Holmgren J, Larsson A., Eur J Pharm Sci. 2012 Aug 29. [Epub ahead of print], Pharmaceutical Technology, Chemical and Biological Engineering, Chalmers University of Technology, SE-41296 Gothenburg, Sweden.

Synopsis:

  • This paper details research towards realization of dry vaccine formulations for sublingual administration, which would be  great boon to both patients and industry “since they are easy to administer and might also have improved stability properties.”
  • This paper presents research using the model protein Ovalbumin in BALB/c mice to determine “the influence of protein release rate from mucoadhesive two-layer tablets on the elicited antibody responses after sublingual immunization.”
  • The authors studied 5 tablet types:
    • Two fast release tablets, one based on a mixture of lactose and microcrystalline cellulose (MCC) and one protein coated ethylcellulose (EC) tablet
    • Three hydrophilic matrix tablets with extended release (ER) properties based on HPMC 90 SH 100000 or Carbopol® 974-P NF
  • What they measured was the in vitro release profiles of the model protein ovalbumin (OVA) from these tablets
  • This was then characterized and correlated to the in vivo potential of the tablets to induce an immune response after sublingual immunization in the BALB/c mice
  • According to the authors, “It could be concluded that a tablet with fast protein release elicits antibody titres not significantly different from titres obtained with OVA in solution, whereas low immune responses were observed with a slow release of OVA from the ER formulations.”
  • Their conclusions:
    • ER tablets seem not favorable for vaccine delivery to the sublingual mucosa
    • A fast releasing tablet formulation has attractive features for sublingual immunization
    • And, of course, that universal statement of all researchers everywhere: “…the use of ER formulations for sublingual vaccination has to be investigated more in detail”

To see the Abstract, and a link to obtain this paper: http://www.ncbi.nlm.nih.gov/pubmed/22959953

 

Take a look at all the topics we research every month for our Literature Search, our Stories, and our Current Awareness Features, and if you don’t see a topic of major interest to you, send me an email [biotext1ster@gmail.com] or text me @ 951-323-4215 and I will add it if it is appropriate to our editorial scope, which is any topic related to the quality, safety, efficacy, or availability of biopharmaceuticals and biologics.

 

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BioQuality, just what you need to know when you need to know it

483s from recent FDA inspections reveal often-cited systemic deficienies

Click the title above to see the whole post. These 483s come from recent issues of BioQuality. Please support us by signing up or subcribing today and telling your colleagues about us. See the links in the box to the right to sign up for a free membership or to subscribe.

The Quality System

Inadequate handling of OOS result for potency of drug product:

  • A retest was performed using the original sample and all results were within specification
  • The lot was then re-sampled with no justification and an additional 3 samples were tested and a range of within-specification results was obtained
  • Original OOS result invalidated without clearly assignable laboratory cause
  • Only the within specification results were reported

The responsibilities and procedures applicable to the quality control unit are not fully followed

The Quality Unit does not review or approve maintenance procedures or records

The Production System

Procedures designed to prevent microbiological contamination of drug products purporting to be sterile are not written and followed, specifically:

  • Vent Filter Integrity Testing is not performed for any of carboy vent filters, and Drug products inside the carboys are considered sterilized material
  • There is no risk assessment that describes the impact of this practice
  • There is lack of written and approved scientific rationale for not integrity testing these vent filters
  • There are no, documents, protocols, studies, validation, and/or qualification records that address the reason why vent filter integrity testing is not performed

Firm demonstrates poor aseptic practices during the filling of sterile products including, but not limited to:

  • An operator performing critical aseptic operations with exposed skin at the forehead, posing an unreasonable risk of the product becoming contaminated
  • Operators moving very quickly in the aseptic area, which may create unacceptable turbulence in the area, and disrupt the unidirectional airflow
  • Operators leaning halfway in and out of the class 100 area while performing interventions over opened bottles

The Facilities and Equipment System

Equipment used in the manufacture, processing, packing or holding of drug products is no of appropriate design and suitably located to facilitate operations for its intended use and cleaning and maintenance

  • Specifically, a number of design and/or structural defects related to equipment or the locatio of equipment in the facility were noted through the course of the inspection including:
    • the fill room for aseptic filling line [redacted by FDA] contains a “U” shaped conveyor belt that makes it necessary for operators to enter the curtained class [redacted by FDA] area of the fill room from the ISO Class [redacted by FDA] area of the fill room by ducking beneath a conveyor belt that is no more than 4 ft high in order to make and/or inspect connections between the surge bottle and the filling machine
    • Monitoring of connections between surge bottle and filling machine is otherwise impaired by a plastic curtain and the distance between the exterior of the conveyor system and the connections

Equipment cleaning validation did not include cleaning agent residue testing

Clean-in-place validation did not include the worst case

Disinfectants used in aseptic processing area and surrounding clean rooms were not rotated

The Laboratory Controls System

Sampling system and method are not appropriate and adequate

  • Firm cannot guarantee that representative samples were collected and appropriately delivered for testing to the microbiology and chemistry laboratories
  • Current sample identification system is inadequate
  • The approach for collecting samples for particulate matter testing independent of the batch size is not scientifically sound
  • There is no written, approved standard operating procedure that describes thoroughly the sorting of samples in the manufacturing area prior to sending them to the respective
  • As a result, the results obtained on each test for finished products may be questionable in that they may not reflect a truly-representative sampling and testing of the filled product
  • In addition, Managers, Supervisors, and other top officials of the Microbiology and other departments could not provide the scientific and statistical rationale behind current sampling practices

The Materials System

Firm failed to reject a lot of components which failed to meet appropriate written specifications, specifically:

  • Lots of Sodium Taurodeoxycholate (TDOC), used to disrupt influenza virus to make a split virion vaccine, were delivered in 2010
  • 15 lots failed the ID test performed, but the lots were accepted for use
  • An investigation was not initiated to determine the reason for identification failures and the vendor was never contacted to inquire about the possible changes to TDOC lots
  • Without further investigation into possible changes to TDOC, the [redacted by FDA] of the lots failing identification were included into the [redacted by FDA] of acceptable [redacted by FDA]

The Packaging and Labeling System

Some labeling on final product packaging was found to be discrepant with labeling on the outer box containing multiple final packages:

  • Specifically, the expiration dates differed by two years

Subscribe to BioQuality and get at least 4 pages of categorize 483s each month and access to the Subscribers Only area of our web site with 483s from 2010 to present

 

BioQuality: just what you need to know, when you need to know it

 

Spanish regulators review European regulatory landscape for cancer vaccines

Cancer immunotherapy products: Regulatory aspects in the European Union.

Hum Vaccin Immunother. 2012 Sep 1;8(9). [Epub ahead of print], Camarero J, Ruiz S., Spanish Medicines Agency; Pharmacology and Clinical Assessment Division; Madrid, Spain.

Synopsis

  • Cancer vaccines, also known as active immunotherapy products are products whose mode of action is to evoke an immune response designed to cause tumor destruction or at least reduce the progression of the tumor.
  • The nature of these products results in certain challenges and difficulties:
    • Quality attributes of these products can be difficult to characterize
    • There is typically a high variability in measurement of quality and other attributes
    • This is especially so for autologous therapies
    • The above complicate interpretation of clinical data
  • Another difficulty according to the authors are the “questions arise in the evaluation of efficacy and safety data in comparison with current chemical or biological treatments for the same indications.”
  •  This review explores the European Union regulatory requirements for such products
  •  Two products, both of which are considered therapeutic cancer vaccines, recently assessed by the regulators are used as examples: Oncophage, for renal cell carcinoma and Provenge, for prostate cancer

To see the Abstract, and a link to obtain this paper: http://www.ncbi.nlm.nih.gov/pubmed/22863755

Take a look at all the topics we research every month for our Literature Search, our Stories, and our Current Awareness Features, and if you don’t see a topic of major interest to you, send me an email [biotext1ster@gmail.com] or text me @ 951-323-4215 and I will add it if it is appropriate to our editorial scope, which is any topic related to the quality, safety, efficacy, or availability of biopharmaceuticals and biologics.

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Access to Medicines

ADME/DMPK  [absorption, distribution, metabolism, and elimination/ drug metabolism and pharmacokinetics]–New! thanks to the reader who suggested this topic

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At the Cutting Edge

Basic Science Relevant to Biopharma and Biologics

Bioanalytical Methods and Issues

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BioQuality, just what you need to know when you need to know it

New Epub on Preclinical Safety Evaluation of Biopharmaceuticals

Thirty years of preclinical safety evaluation of biopharmaceuticals: did scientific progress lead to appropriate regulatory guidance?

Kooijman M, J K van Meer P, H M Moors E, Schellekens H, Expert Opin Drug Saf. 2012 Sep;11(5):797-801. Epub 2012 Aug 6., Utrecht University, Copernicus Institute of Sustainable Development, Innovation studies , Heidelberglaan 2, postbus 80115, 3508 TC, Utrecht , The Netherlands +31 30 253 6771 ; +31 30 251 2746 ; m.kooijman@uu.nl.

Synopsis

  • Due to complexity and other attributes of biopharmaceuticals, it was and is expected that “classical preclinical safety evaluation procedures applied to SMTs would not predict the adverse effects of biopharmaceuticals.” [ed. note: SMT is an abbreviation for Small Molecule Therapeutics]. “Therefore,” the authors go on to say, “until sufficient experience was gained, the preclinical safety evaluation of biopharmaceuticals was carried out on a case-by-case basis.”
  • This Epub reviews the past 30 years, since the first biopharmaceuticals were developed, of preclinical safety experience, and tracks its evolution. Their thoughts, opinions, and conclusions include:
    • Our knowledge has now reached the point that a “preclinical safety evaluation procedure suited to biopharmaceuticals” is now a reasonable hope
    • According to the authors, this experience “shows that, as result of the risk-averse behavior of regulators and industry, classical procedures were taken as starting point although state-of-the-art knowledge on biopharmaceuticals was directed towards creating a new procedure, driven by the specific properties of biopharmaceuticals.”
    • The authors criticize current Regulatory Guidance for the preclinical safety evaluation of biopharmaceuticals because, in their opinion, “it employs a checkbox approach.”
  • They conclude by reminding us that “The adverse effects induced by biopharmaceuticals are on-target or immune system-induced,” and therfore: “the preclinical safety evaluation should not be standardized, but rather driven by product specific safety concerns.”

To see the Abstract, and a link to obtain this paper:  http://www.ncbi.nlm.nih.gov/pubmed/22861668 

Take a look at all the topics we research every month for our Literature Search, our Stories, and our Current Awareness Features, and if you don’t see a topic of major interest to you, send me an email [biotext1ster@gmail.com] or text me @ 951-323-4215 and I will add it if it is appropriate to our editorial scope, which is any topic related to the quality, safety, efficacy, or availability of biopharmaceuticals and biologics. And please support BioQuality by subscribing. See the link at right to go to our Home Page where you will find the subscription link.

Our Current Search Topics:

Access to Medicines

ADME/DMPK  [absorption, distribution, metabolism, and elimination/ drug metabolism and pharmacokinetics]–New! thanks to the reader who suggested this topic

Adverse Event Monitoring and Reporting

Analytical Methods for Characterization and Control

Anti-drug Antibodies and Unwanted Immunogenicity

At the Cutting Edge

Basic Science Relevant to Biopharma and Biologics

Bioanalytical Methods and Issues

Biological Potency, Activity, and other Biological Assays

Biomarkers

Biosimilars, Follow-on Biologics, FOPPs, Biobetters, etc.

Carbohydrate/Glycan/Oligosaccharide/Polysaccharide Characterization and Analysis

Cellular Therapies and Regenerative Medicine

Clinical Issues

Combination Products– New! thanks to the reader who suggested this topic

Container/Closure Issues

Data Analysis, Mathematical Models and Statistics

Development Costs

Development Issues, Concerns, Strategies, etc.

Deviations, Handling and Reporting

Discovery Research

Distribution Issues

European Regulations and Regulatory Perspective

Excipient Analysis and Control

Formulation and Delivery

Gene and other Nucleic Acid Therapy

General Business Issues

GMP Compliance, General

Good Distribution Practice

Host Cell Proteins

Laboratory Issues

Manufacturing and Production Issues

Method Qualification and Validation

Microbial Analysis and Control

Molecular and Personalized Medicine

Nanomedicine and Biopharmaceuticals– New! thanks to the reader who suggested this topic

Nucleic Acids

Particulate Analysis and Issues

Personalized and Molecular Medicine

Preclinical Issues

Process Monitoring, and Control, Process Analytical Technology (PAT)

Process Development

Product Development, Pre-clinical and Clinical

Protein, Glycoprotein, Peptide, and Other Bio-molecule Structure/Function

Proteins, Glycoproteins, Peptides, Antibodies and Other Biomolecules: Characterization, Analysis, and Control

Quality by Design (QbD)

Raw Material Analysis and Control

Regenerative Medicine

Regulations, General Considerations

Regulatory Agencies

Regulatory Submissions, Review, Reporting, etc.

Reference Standard Qualification and Verification

Risk Analysis and Management

Safety and Efficacy Issues

Separation Science

Stability, Aggregation, and Degradation Issues

Surveillance and Pharmacovigilance

Vaccine Development, Testing, Control, Production, Delivery, Stability

Validation

BioQuality, just what you need to know when you need to know it

Pre-clinical Studies for Cellular Therapies: CBER Office of Cellular, Tissue and Gene Therapy Director Discusses FDA Expectations

Dr. Celia Witten, Director of the Office of Cellular, Tissue and Gene Therapy at FDA Center for Biologics Evaluation and Research, otherwise known as CBER, gave a talk at a recent FDA workshop on FDA’s twin role with regards to cellular therapies. Here are some of the points she made:

  • “Just to make a comment about our mission, everybody thinks of FDA as being the organization responsible for regulation and protecting public health by looking at safety and efficacy. We also do have as part of our formal mission statement advancing public health by helping to speed innovations and our efforts with groups like this one that have dialogue with the scientific community Is part of our way of accomplishing that innovations part of our mission.”
  • ” what i want to highlight is this, our program priority, the highest program priority for this year is publishing a draft guidance for cellular an gene therapy products so I hope that we — I can make no promises about timing but I hope we’re able to come up with that sometime this this calendar year.”

She also gave a recap of a previous meeting, so that all attendees could be ‘on the same’ page when it comes the topics discussed at this, the second in a series of FDA meetings on cellular therapies. Some of her  take-away messages from that first meeting included:

  • Issues surrounding Consent are looming large and there a draft rules being drawn up based on discussions with a variety of stakeholders
  • It is important, for cellular, as well as for more traditional therapuetics, “to do pre-clinical studies with the product you’re going to finally manufacture by the process you have already manufactured (product with)”
  • “you have the think about going towards the clinical trial in terms of manufactured product, in terms of thinking about sourcing, derivation of the cells, sort the cells, engineer the cells depending on what the end goal is and perform pre-clinical studies, clinical studies an apply for license insure of new drug”

 

See our August Issue for more details on this important talk!  It is our lead story. To Subscribehttps://www.formstack.com/forms/bqform-subscription

 

FDA Issues Multinational Warning Letter

14 Page Letter for Sanofi-Pasteur in Canada and France

From the June/July Issue of BioQuality

Sanofi-Pasteur in Canada and France received a 14 page joint warning letter from the USFDA last week. Twenty-four items were specifically written for the facility in Toronto, Canada and two items for the Marcy l’Etoile, France facility. Additionally the letter reviewed 20 inadequate 483 responses from the firms. To read the entire story and see our bullet point summary and analysis of this important WL, become a BioQuality subscriber–all current and back issues of BQ are available for subscribers to view or download. Plus, there are bullet point summaries of 483s from FDA inspections of biopharma and biologics firms (from 2010 – present, with more back years to come soon).

To see the Warning Letter: Click Here

Amgen Scientists Publish New Tool to Aid Selection of rProtein Leads

Productivity and Quality of Recombinant Proteins Produced by Stable CHO Cell Clones can be Predicted by Transient Expression in HEK Cells (click the large title above to see the whole post)

 

Mol Biotechnol. 2012 Aug 23. [Epub ahead of print], Diepenbruck C, Klinger M, Urbig T, Baeuerle P, Neef R., Amgen Research (Munich) GmbH, Staffelseestr. 2, 81477, Munich, Germany.

 

Bullet-point Overview:

  • The authors describe an approach that allows prediction of the productivity and quality of recombinant proteins by stable producer cell clones with the help of transient transfection studies
  • As examples, they presented results from three distinct bispecific T cell engager (BiTE(®))-a new class of single-chain antibody-based therapeutics showing very promising results in the treatment of cancer
  • They found that BiTE(®) titers of transiently transfected HEK cells showed a striking correlation with titers of selected stable CHO cell clones
  • In addition, the percentage of the monomeric BiTE(®) fraction in cell culture supernatants correlated well between transiently expressing HEK and stably expressing CHO cell clones
  • According to the authors, this validates the use of transient transfection studies for the selection of biopharmaceutical lead candidates with desired pharmaceutical properties

 

To see the Abstract, and a link to obtain this paper: http://www.ncbi.nlm.nih.gov/pubmed/22915356

 

Subscribe to BioQuality and stay on top of the important Regulatory and Technical literature (see the link to subscribe on the Member’s Page or our Home Page). The topics we cover include:

  • Adverse Event Monitoring and Reporting
  • Analytical Methods for Characterization and Control
  • Anti-drug Antibodies and Unwanted Immunogenicity
  • At the Cutting Edge
  • Basic Science Relevant to Biopharma and Biologics
  • Bioanalytical Methods and Issues
  • Biological Potency, Activity, and other Biological Assays
  • Biomarkers
  • Biosimilars, Follow-on Biologics, FOPPs, Biobetters, etc.
  • Carbohydrate/Glycan/Oligosaccharide/Polysaccharide Characterization and Analysis
  • Cellular Therapies and Regenerative Medicine
  • Clinical Issues
  • Container/Closure Issues
  • Data Analysis, Mathematical Models and Statistics
  • Development Costs
  • Development Issues, Concerns, Strategies, etc.
  • Deviations, Handling and Reporting
  • Discovery Research
  • Distribution Issues
  • European Regulations and Regulatory Perspective
  • Excipient Analysis and Control
  • Formulation and Delivery
  • Gene and other Nucleic Acid Therapy
  • General Business Issues
  • GMP Compliance, General
  • Good Distribution Practice
  • Host Cell Proteins
  • Laboratory Issues
  • Manufacturing and Production Issues
  • Method Qualification and Validation
  • Microbial Analysis and Control
  • Molecular and Personalized Medicine
  • Nucleic Acids
  • Particulate Analysis
  • Personalized and Molecular Medicine
  • Preclinical Issues
  • Process Monitoring, and Control, Process Analytical Technology (PAT)
  • Process Development
  • Product Development, Pre-clinical and Clinical
  • Protein, Glycoprotein, Peptide, and Other Bio-molecule Structure/Function
  • Proteins, Glycoproteins, Peptides, Antibodies and Other Biomolecules: Characterization, Analysis, and Control
  • Quality by Design (QbD)
  • Raw Material Analysis and Control
  • Regenerative Medicine
  • Regulations, General Considerations
  • Regulatory Agencies
  • Regulatory Submissions, Review, Reporting, etc.
  • Reference Standard Qualification and Verification
  • Risk Analysis and Management
  • Safety and Efficacy Issues
  • Separation Science
  • Stability Issues
  • Surveillance and Pharmacovigilance
  • Vaccine Development, Testing, Control, Production, Delivery, Stability
  • Validation

 

Don’t see your favorite Biopharma/Biologics topic? Send me an email: biotech1ster@gmail.com and I will add it to my searches (if it is consonant with our ed policy, of course)

CDER Small Business Webinar

Building Quality into Clinical Trials – an FDA Perspective

FDA has made slides available from a recent CDER Small Business Webinar titled Building Quality into Clinical Trials – an FDA Perspective. Topics covered during the webinar include:

• Background – why we are talking about “building in quality”?

o Increasing concerns regarding the safety of medical products

o Increasing complexity of medical products and studies

o Multisite, international studies

o Recognition that we cannot monitor or inspect in quality

• Objectives and responsibilities of FDA’s bioresearch monitoring (BIMO) program

• The Quality Systems Approach

• Elements of a quality system – and how they are related to FDA regulations

o What is “Quality”?

o What are the elements of a quality clinical study?

• Building in quality from the start – and improving on-going studies

• Clinical Trial Transformation Initiative (CTTI)

Some salient points made during the webinar:

• BIMO:

o Generally inspects after studies completed, though they are shifting more resources to “real-time” inspections

o Inspects selected study sites – may not be able to extrapolate findings to overall study

• There is a shared responsibility for quality, but the quality systems approach emphasizes the responsibility of management at the sponsor

• Quality is the ability to:

o Effectively and efficiently answer the intended question about the benefits and risks of a medical product (therapeutic or diagnostic) or procedure

o While Ensuring protection of human subjects

• Adequate Monitoring by the sponsor involves:

o Assuring investigators’ compliance with the investigational plan and regulations

o Reviewing adverse events and determine impact on continuation of the study

o Assuring investigators collect and maintain current, complete, and accurate data

• Suggestions for a quality study – the regulations and beyond:

o Select qualified investigators

o Assure protocol & data requirements optimized

o Provide adequate training

o Stress importance of informed consent process

o Ensure adequate monitoring

o Ensure investigator compliance

o Ensure any and all contracted 3rd parties comply with the appropriate regulations

To read a brief description of the webinar, and to view or download the 46 slides see the links here: http://www.fda.gov/Drugs/DevelopmentApprovalProcess/SmallBusinessAssistance/ucm303135.htm

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