Angie Drakulich was editorial director of Pharmaceutical Technology.

Angie Drakulich

The US Food and Drug Administration plans to begin collecting information for its Sentinel Initiative, according to a Sept. 4 

 announcement. The initiative, established in May 2008, focuses on enabling FDA to improve monitoring of drug performance after marketing approval by working with multiple healthcare data systems. The 2007 Food and Drug Administration Amendments Act calls for the agency to be able to access data from 25 million patients by July 2010, and from 100 million patients by July 2012, according to the announcement.
  
 “The proposed system will enable queries of distributed data sources quickly and securely for relevant product-safety information,” says the announcement. “Data will continue to be managed by its owners, and only data of organizations who agree to participate in this system will be included.”
  
 The call for data, which will help FDA plan for this proposed system and for future work related to the Sentinel Initiative, has been submitted for approval to the Office for Management and Budget. The data sought includes the scope, content, structure, quality, and timeliness of data; patient population(s), duration of followup, and capture of care across all settings; availability, experience, and interest of investigators with knowledge of the data in using it for postmarket product-safety surveillance as well as plans for further data source enhancements; availability, experience, and interest of investigators with knowledge of the data in participating in a distributed data system; and barriers that exist to including each data source in the Sentinel Initiative.
  
The agency estimates that each respondent submitting the above information will spend about 24.5 hours doing so. FDA expects 250 respondents will participate in the survey.

FDA Issues First Sentinel Initiative Project Report: Statistical Methods

Articles

The US Food and Drug Administration plans to begin collecting information for its Sentinel Initiative, according to a Sept. 4 Federal Register announcement.

FDA Seeks Data for Sentinel Initiative

Later this month, Dr Barbara Jentges, the Managing Director at PhACT GmbH, a regulatory consulting and training firm based in Duggingen (Switzerland), will be speaking at the 2nd Vetter Drug Management Leadership Conference in Germany. 

 spoke with her about changing regulatory expectations, with a focus on Europe.

Q1: The global pharmaceutical market is undergoing a tremendous shift as we enter the age of personalized medicine based on biologics, cell products and improved diagnostics. In your experience, how are regulators coping with this shift and what types of changes are they making themselves? 


Regulators are monitoring scientific development and are constantly reviewing the legislation in light of new technologies and therapies. Apart from safeguarding medicinal products, it is a necessity to provide an economic and regulatory environment to bring novel treatments to the patients as early as possible. One example of how regulators are coping with this challenge is with Advanced Therapy Medicinal Products (ATMPs). This group of new technologies and therapies is based on genes (gene therapy), cells (cell therapy), and tissues (tissue engineering) and has the potential to treat a number of severe diseases. 

In the past, the lack of an EU-wide regulatory framework for these cell-based products led to divergent national approaches. With the Advanced Therapies Regulation that took effect 30 December 2008, an EU harmonized regulation has been achieved. The main elements of this new regulation are a mandatory centralized application procedure for ATMPs marketing approval, technical requirements considering the specific characteristics of these products, and the establishment of a Committee for Advanced Therapies within the European Medicines Agency (EMEA). Additionally, the regulation provides special incentives for small- and- medium-sized enterprises such as facilitated access and reduced fees for scientific advice.

Q2: There has been a greater willingness among the global regulatory authorities to harmonize regulations over the past few years, demonstrated by the final approval of the ICH Quality Trio guidelines (Q10 Pharmaceutical Quality System, Q9 Quality Risk Management; and Q8 Pharmaceutical Development). Do you think individual authorities are also becoming more willing to share information regarding inspections, for example, with each other? Are they willing to give up some domestic regulatory autonomy in order to apply a more harmonized approach? 


It is indeed the intention of inspectorates and in the best interest of the pharmaceutical industry to share information on inspections to save significant resources on both sides. The EU has set up the EudraGMP database to share information about manufacturing and importation authorizations and GMP certificates, PIC/S is discussing opportunities to exchange inspection information, and the EU and US have entered into a cooperation in this field via a pilot program. The recently released version of the EudraGMP (version 2.0) provides public access to information about manufacturing and importation authorizations as well as GMP certificates. (

Q3: International Conference on Harmonization representatives also adopted the electronic Common Technical Document (eCTD), allowing pharmaceutical companies to submit information electronically to the various regulatory authorities. Authorities are supposed to be ready to take eCTDs only (with no paper submissions) by the end of this year. Are they ready? Is industry ready? 


In Europe, EMEA will mandate the use of the eCTD format for the centralized procedure for all electronic-only submissions for all applications (new and existing) and all submission types as of Jan. 1, 2010. Non-eCTD format electronic submissions will be rejected. Although paper-only submissions may be accepted alternatively, this type of submission may lead to significant handling and review issues.

According to an EU eCTD Implementation Survey that covered the period from July 2007 to June 2008, only 1% of all applications in Europe used eCTD format. As for EU member states, the survey revealed that 28% of the authorities did not specify when they will be ready to accept eCTDs. Although both sides need to overcome a number of obstacles, the way to a paperless submission and life cycle management will soon be standard.

Q4: Can you talk about the benefits as well as the challenges that come with eCTD implementation? For example, it seems that applicants still have to submit different information to each region’s authority. 


One of the major benefits of the eCTD’ is the paperless submission, but that’s not all.  The eCTD is meant to reduce costs in the administration, assessment, and archiving of marketing authorization applications for medicines. However, the implementation of an eCTD requires the creation of a suitable IT infrastructure as well as the commitment to workflow changes and long-range strategic planning. Additionally, new processes need to be considered (e.g., for making the documents ‘eCTD-ready’ by including a number of navigation tools such as hyperlinking and bookmarking). Once a system has been established, further challenges are ahead. Regionally different requirements need to be considered when building eCTDs for the EU, US, and Japan. For example, Study Tagging Files are required for a US-eCTD, but not for a EU-eCTD, and not allowed in Japan. 

Q5: Do you see more changes ahead with regard to what regulators expect from industry and in terms of compliance?  


It was one of the intentions of ICH Q8, Q9, and Q10 to move away from pure compliance to a risk-based, scientific approach. With that in mind, interaction and communication between industry and regulators need to be intensified to find the safest solution for the patient and thus must balance out efficient manufacturing. Costs need to be controlled on both sides to manage the health system of the society by ensuring compliance with regulations.

Barbara Jentges, the Managing Director at PhACT GmbH, a regulatory consulting and training firm in Switzerland, speaks about changing regulatory expectations &#151; with a focus on Europe.

Q&A: changing regulatory expectations in Europe

Later this month, Barbara Jentges, PhD, the managing director at PhACT, a regulatory consulting and training firm based in Duggingen, Switzerland, will be speaking at the second Vetter Drug Management Leadership Conference in Germany. 

 The global pharmaceutical market is undergoing a tremendous shift as we enter the age of personalized medicine based on biologics, cell products, and improved diagnostics. In your experience, how are regulators coping with this shift and what types of changes are they making themselves?

 Regulators are monitoring scientific development and are constantly reviewing the legislation in light of new technologies and therapies. Apart from safeguarding medicinal products, it is a necessity to provide an economic and regulatory environment to bring novel treatments to the patients as early as possible. One example of how regulators are coping with this challenge is with Advanced Therapy Medicinal Products (ATMPs). This group of new technologies and therapies is based on genes (i.e., gene therapy), cells (i.e., cell therapy), and tissues (i.e., tissue engineering) and has the potential to treat a number of severe diseases.

  In the past, the lack of a European Union-wide regulatory framework for these cell-based products led to divergent national approaches. With the Advanced Therapies Regulation that took effect Dec. 30, 2008, an EU harmonized regulation has been achieved. The main elements of this new regulation are a mandatory, centralized application procedure for ATMPs marketing approval, technical requirements considering the specific characteristics of these products, and the establishment of a Committee for Advanced Therapies within the European Medicines Agency (EMEA). Additionally, the regulation provides special incentives for small- and medium-sized enterprises such as facilitated access and reduced fees for scientific advice.

 There has been a greater willingness among the global regulatory authorities to harmonize regulations over the past few years, demonstrated by the final approval of the ICH Quality Trio guidelines (Q10 Pharmaceutical Quality System, Q9 Quality Risk Management, and Q8 Pharmaceutical Development). Do you think individual authorities are also becoming more willing to share information regarding inspections, for example, with each other? Are they willing to give up some domestic regulatory autonomy in order to apply a more harmonized approach?

 It is indeed the intention of inspectorates and in the best interest of the pharmaceutical industry to share information on inspections to save significant resources on both sides. The EU has set up the EudraGMP database to share information about manufacturing and importation authorizations and good manufacturing practice (GMP) certificates, PIC/S is discussing opportunities to exchange inspection information, and the EU and US have entered into a cooperation in this field via a pilot program. The recently released version of the 

 (version 2.0) provides public access to information about manufacturing and importation authorizations as well as GMP certificates.

 International Conference on Harmonization representatives also adopted the electronic Common Technical Document (eCTD), thus allowing pharmaceutical companies to submit information electronically to  various regulatory authorities. Authorities are supposed to be ready to take eCTDs only (with no paper submissions) by the end of this year. Are they ready? Is industry ready?

 In Europe, EMEA will mandate the use of the eCTD format for the centralized procedure for all electronic-only submissions for all applications (new and existing) and all submission types as of Jan. 1, 2010. Non-eCTD format electronic submissions will be rejected. Although paper-only submissions may be accepted alternatively, this type of submission may lead to significant handling and review issues.

  According to an EU eCTD Implementation Survey that covered the period from July 2007 to June 2008, only 1% of all applications in Europe used the eCTD format. As for EU member states, the survey revealed that 28% of the authorities did not specify when they will be ready to accept eCTDs. Although both sides need to overcome a number of obstacles, the way to a paperless submission and life-cycle management will soon be standard.

 Can you talk about the benefits as well as the challenges that come with eCTD implementation? For example, it seems that applicants still have to submit different information to each region’s authority.

 One of the major benefits of the eCTD is the paperless submission, but that’s not all. The eCTD is meant to reduce costs in the administration, assessment, and archiving of marketing-authorization applications for medicines. However, the implementation of an eCTD requires the creation of a suitable information technology infrastructure as well as the commitment to workflow changes and long-range strategic planning. Additionally, new processes need to be considered (e.g., for making the documents ‘eCTD-ready’ by including a number of navigation tools such as hyperlinking and bookmarking). Once a system has been established, further challenges are ahead. Regionally different requirements need to be considered when building eCTDs for the EU, US, and Japan. For example, Study Tagging Files are required for a US eCTD, but not for an EU eCTD, and the files are not allowed in Japan.

 Do you see more changes ahead with regard to what regulators expect from industry and in terms of compliance?

  It was one of the intentions of ICH Q8, Q9, and Q10 to move away from pure compliance to a risk-based, scientific approach. With that in mind, interaction and communication between industry and regulators need to be intensified to find the safest solution for the patient and thus must balance out efficient manufacturing. Costs need to be controlled on both sides to manage the health system of the society by ensuring compliance with regulations.

Later this month, Dr. Barbara Jentges, the managing director at PhACT GmbH, a regulatory consulting and training firm based in Duggingen, Switzerland, will be speaking at the 2nd Vetter Drug Management Leadership Conference in Germany.

Q&A With Compliance Expert Barbara Jentges

Conference in Philadelphia, in August, Brian K. Nunnally, associate director of process validation at Wyeth (Madison, NJ), and John McConnell, principal of the Australian consulting firm Wysowl, tried to hammer the "go/no–go" mindset out of the brains of the pharmaceutical industry members in attendance. Their talks were based on the principles within the US Food and Drug Administration's draft guidance, 

Process Validation: General Principles and Practices

, issued in November 2008, and the quality-by-design and process-analytical-technology approaches cascading over industry. Currently, industry tends to wait for a failure before it takes action—pharma is the only industry like that, said McConnell. Instead of studying the out-of-specification (OOS) point, "we need to study where the process began to go out of whack—usually about 15 batches before the actual OOS point occurred," he explained. "Meeting spec should not be the end point, but rather a beginning expectation. Our job is to reduce variability way 

Nunnally added that when the final guidance comes out, industry will need to understand the sources of its product variation and control that variation commensurate with the risks involved. Industry can no longer say a batch is "good" or "not good"  based on end-product testing. "Proper control charting can help us see OOS in a different way ... by looking at it in three forms: process, sample, and analytical." 

Both speakers reiterated that the benefit of reducing variability is increased capability. The challenge, however, is changing industry's mindset.  "Learning is easy," said McConnell, "unlearning is the hard part."  

As new process validation guidelines emerge, industry needs to reinvent how it releases product.

The Go/No-Go Mindset

The FDA has said it would like to amend postmarket safety reporting regulations “to require that manufacturers and other facilities subject to current reporting requirements submit their reports in an electronic format".

One of two new proposed rules affecting drugs and biologics asks companies to submit adverse experience reports electronically so that the agency can process, review, archive and retrieve critical information in a more efficient and effective way. The types of adverse events that must be reported remain the same. The second rule applies to adverse events for medical devices.

Currently, reports are submitted on paper and entered into the FDA system manually. “Both proposed rules will improve the agency’s ability to obtain safety information more quickly, which will help lead to faster identification of potential safety problems. Information obtained from these reports may be critical to future action that improves patient safety,” said David Buckles, Director of the Division of Postmarket Surveillance at the FDA’s Center for Devices and Radiological Health (CDRH), in the release.

The agency’s Center for Drug Evaluation and Research and Center for Biologics Evaluation and Research began a pilot program in 2000 to allow manufacturers to submit electronic adverse event reports through the FDA’s Electronic Submission Gateway or on CD-ROM, digital tape or floppy disk. The International Conference on Harmonization (ICH M4) defines standards for these submissions. Under the proposed rule for drugs and biologics, firms will be able to submit electronic reports using ICH standards or through a new safety reporting web portal that FDA is developing.  Firms that wish to use the gateway will need to obtain an electronic certificate from the agency first.

Not covered in the proposed rule for drugs and biologics are: "safety reports filed under an investigational new drug application, annual reports that manufacturers submit to FDA on approved drugs and biologics, biologic product deviation reports, reports of complications of blood transfusion and collection confirmed to be fatal, and certain reports on human cells, tissues and cellular and tissue-based products."

The FDA has said it would like to amend postmarket safety reporting regulations ?to require that manufacturers and other facilities subject to current reporting requirements submit their reports in an electronic format".

FDA seeks mandatory electronic safety reporting

The US Food and Drug Administration announced in an Aug. 20, 2009 

 that it would like to amend postmarket safety reporting regulations “to require that manufacturers and other facilities subject to current reporting requirements submit their reports in an electronic format.”

  One of two new proposed rules affecting drugs and biologics asks companies to submit adverse experience reports electronically so that the agency can process, review, archive, and retrieve critical information in a more efficient and effective way. The types of adverse events that must be reported remain the same. The second proposed rule applies to adverse events for medical devices. 

  Currently, reports are submitted on paper and entered into the FDA system manually. “Both proposed rules will improve the agency’s ability to obtain safety information more quickly, which will help lead to faster identification of potential safety problems. Information obtained from these reports may be critical to future action that improves patient safety,” said David Buckles, Ph.D., director of the Division of Postmarket Surveillance at the FDA’s Center for Devices and Radiological Health (CDRH), in the release. 

  The agency’s Center for Drug Evaluation and Research and Center for Biologics Evaluation and Research began a pilot program in 2000 to allow manufacturers to submit electronic adverse event reports through FDA’s Electronic Submission Gateway or on CD-ROM, digital tape, or floppy disk. The International Conference on Harmonization (ICH M4) defines standards for these submissions. Under the proposed rule for drugs and biologics, firms will be able to submit electronic reports using ICH standards or through a new safety reporting Web portal that FDA is developing.  Firms that wish to use the gateway will need to obtain an electronic certificate from the agency first. 

  Not covered in the proposed rule for drugs and biologics are:  “safety reports filed under an investigational new drug application, annual reports that manufacturers submit to FDA on approved drugs and biologics, biologic product deviation reports, reports of complications of blood transfusion and collection confirmed to be fatal, and certain reports on human cells, tissues and cellular and tissue-based products.”

The US Food and Drug Administration announced in an Aug. 20, 2009 release that it would like to amend postmarket safety reporting regulations "to require that manufacturers and other facilities subject to current reporting requirements submit their reports in an electronic format."