Angie Drakulich was editorial director of Pharmaceutical Technology.

Angie Drakulich

Two years ago, the US Food and Drug Administration’s Office of Generic Drugs (OGD) developed and implemented a program to test question-based reviews for abbreviated new drug applications (ANDAs). OGD is reviewing the benefits and challenges faced by pharmaceutical firms involved in the initiative to see what changes need to be made going forward. 

 spoke to Dr. Aloka Srinivasan, team leader at OGD, about the lessons learned and what industry should expect next.

 OGD initiated the question-based review (QbR) process for submitting quality overall summaries (QOS) within ANDAs in 2007. What was the primary reason for this initiative?
  
 

The question-based review initiative by the Office of Generic Drugs was undertaken to implement the concepts and principles of FDA’s CGMPs for the 21st Century initiative. A second reason for QbR was the ever-increasing workload at OGD. The expectation in OGD is that, by seeking the industry’s response to the critical questions regarding justification for establishing controls, we may be able to reduce the number of deficiencies cited and eventually cut down on the review time. 
  
 

 How many firms submitted QbR applications for ANDAs during the past two years?
  
 

Currently, almost all the ANDAs submitted to OGD have the question-based review–quality overall summary (QbR-QOS) in Module 2 of the CTD format. We acknowledge the support and cooperation of the generic industry in this respect.
  
 

 One clear benefit of QbR is the flexibility it allows pharmaceutical firms in defining and justifying the choices they have made when formulating a product. What other benefits does QbR offer industry?
  
 

I think that a generic industry representative is in a better position to respond to this question. However, based on the feedback we have received from the industry, QbR has helped them in sharing and justifying the information in the submissions, which is generally considered critical for product performance. The QbR has also set the baseline to direct the generic industry toward quality by design (QbD).
 

 Were any benefits gained on the review side for OGD?
  
 

The reviewers of OGD have benefited greatly from QbR-QOS. The product and process development summaries in QbR-QOS have provided insight into the sponsor’s rationale for product design and development of manufacturing process. Justifications provided in QbR-QOS also have lead to better understanding of the product and process and has reduced the number of deficiencies communicated to ANDA sponsors. Electronic QbR-QOS has saved documentation time and reduced transcriptional errors and assessment time beyond primary review.
 

 Several challenges were identified during the QOS-QbR pilot period as well. For instance, FDA reviewers found that many firms did not fully fill out the product and process development section (Module 3 in the QbR). In addition, some firms justified their choices with a “quality by testing” approach rather than a “quality by design” approach. Why do you think these problems occurred, and what do they mean for the QbR process going forward?
  
 

In OGD, we consider these as “growing pains” which are common with any shift of paradigm. We are seeing more and more ANDAs with better responses to the questions in QbR-QOS and relevant information regarding pharmaceutical development in the body of data. 
 

 What should industry expect next for QbR-based submissions for generic drugs? 
  
 

OGD is working closely with the generic drug industry to move the QbR base submission to the next level; to implement the principles of QbD in the development of the generic products.  OGD and the Generic Pharmaceutical Association (GPhA) had a two-day meeting recently to discuss the implementation of QbD for the generic drug industry. The industry’s response to this initiative was very positive.  OGD is expecting that this combined effort will provide a QbD platform to address the pharmaceutical development of the generic products.
 

 Dr. Srinivasan will be presenting an FDA Keynote Address at 

’s 3rd Annual Conference next month in Philadelphia. She’ll be discussing the new paradigm for generic drug applications and reviews.
  
 To register or to get more information about 

 3rd Annual Conference (Aug. 11-12, Philadelphia, PA), visit the 

FDA Office of Generic Drugs Question-Based Review Initiative: An Update

 (Journal of Validation Technology article)
  
 

Opinions expressed in this interview are those of the authors and do not necessarily reflect the views or policies of the FDA.
 

Articles

Two years ago, the US Food and Drug Administration's Office of Generic Drugs (OGD) developed and implemented a program to test question-based reviews for abbreviated new drug applications (ANDAs). OGD is reviewing the benefits and challenges faced by pharmaceutical firms involved in the initiative to see what changes need to be made going forward.

FDA's Dr. Srinivasan Discusses Question-based Reviews for Generic Drugs

The US Food and Drug Administration issued a draft guidance for industry, 

Incorporation of Physical-Chemical Identifiers into Solid Oral Dosage Form Drug Products for Anticounterfeiting

, on July 13. The draft guidance focuses on the use of inks, pigments, flavors, and other physical-chemical identifiers (PCIDs) to make drug products more difficult to duplicate by counterfeiters, and to make it easier to identify the genuine version of the drug, according to an FDA 

“Drug counterfeiting is a serious public health concern,” said FDA Commissioner Margaret A. Hamburg in the release. “We look forward to working with industry to help ensure that consumers are not exposed to products containing unknown, ineffective, or harmful ingredients.”

According to the press release, PCID is defined as “a substance or combination of substances possessing a unique physical or chemical property used to identify and authenticate a drug product or dosage. In addition to inks, pigments, and flavors, specific chemicals may be used as molecular tags in a PCID.” 

The draft guidance recommends that drug manufacturers use the lowest level of PCID possible and to ensure that the PCID used has no medicinal effect. The PCID should be placed within the dosage form to avoid interaction with the drug’s active ingredient, according to the press release. 

PCIDs can be easily detected in most cases by wholesalers or pharmacists to determine a product’s authenticity, but occasionally, analytical instruments are necessary to identify a PCID within a product. FDA believes that many potential PCIDs are already in use as food additives, colorants, or other types of inactive ingredients with established safety profiles, according to the release.

Comments on the draft guidance can be submitted electronically to FDA.

The US Food and Drug Administration issued a draft guidance for industry, Incorporation of Physical-Chemical Identifiers into Solid Oral Dosage Form Drug Products for Anticounterfeiting, on July 13.

Physical Chemical Identifiers Play a Role in New FDA Anticounterfeiting Draft Guidance

  on its anticompetitive inquiry into the pharmaceutical sector on July 8, 2009. The inquiry began in January 2008 to investigate possible anticompetitive conditions

in the pharmaceutical sector, specifically  looking at why fewer new medicines were being brought to market in the European Union and why generic entry seemed to be delayed in some cases. 

 on its preliminary report , which was issued in November 2008. 

After reviewing a sampling of pharmaceutical drugs that faced exclusivity expiration between 2000 and 2007 in 17 EU countries, the inquiry team found that “citizens waited more than seven months after patent expiry for cheaper generic medicines, costing them 20% in extra spending.” Other major findings according to an EC 

Originator companies use a variety of instruments to extend the commercial life of their products without generic entry for as long as possible

There is a decline of novel medicines reaching the market, perhaps based on certain company practices

Further market monitoring is needed to identify all the factors that contribute to this decline in innovation.

The European Commission intends to increase scrutiny under the EC Treaty antitrust law and bring specific cases where appropriate, according to the release. The inquiry panel also recommended the following: 

The establishment of a community patent and a unified specialized patent litigation system in Europe to reduce administrative burdens and uncertainty for companies (this is based on the report’s finding that 30% of patent court cases are conducted in parallel in several EU member states, and in 11% of cases, national courts reach conflicting judgements).

The welcoming of recent initiatives by the European Patent Office, including limiting the possibilities and time periods during which voluntary divisional patent applications can be filed, to ensure a high quality standard of patents granted and to accelerate procedures. 

Ensuring that third-party submissions do not occur or lead to delays for generic drug approvals

Significantly accelerating approval procedures for generic medicines 

Taking action if misleading information campaigns questioning the quality of generic medicines are detected in their territory

Streamlining trials that test the added value of novel medicines.

"We must have more competition and less red tape in pharmaceuticals. The sector is too important to the health and finances of Europe's citizens and governments to accept anything less than the best,” said Neelie Kroes, European commissioner for competition, in a statement on the European Commission 

“The inquiry has told us what is wrong with the sector, and now it is time to act. When it comes to generic entry, every week and month of delay costs money to patients and taxpayers. We will not hesitate to apply the antitrust rules where such delays result from anticompetitive practices. The first antitrust investigations are already under way, and regulatory adjustments are expected to follow dealing with a range of problems in the sector."

These changes, meant to provide EU citizens with quicker access to safe, innovative and affordable medicines, are expected to take effect immediately.

European Commission Report: Originators Block Generic Competition

The European Commission adopted the final report on its anticompetitive inquiry into the pharmaceutical sector on July 8, 2009.

Europe Issues Anticompetitive Inquiry Report

The National Institutes of Health (NIH) issued on July 7, 2009, 

 for human stem-cell research that widen the door to the cell lines that can be used if they meet certain ethical requirements. Based on President Barack Obama’s March 9 executive order to reinstate and increase federal funding of research involving human stem-cell research, the guidelines provide final rules on conducting “responsible, scientifically worthy human stem-cell research, including human embryonic stem-cell (hESC) research.” Taking effect on July 7, the guidelines apply to NIH funds for research using hESCs and certain uses of induced pluripotent stem cells.

The guidelines have taken into account public comments received in April and May 2009 based on NIH’s draft guidelines, which were issued on Apr. 23, 2009. NIH received approximately 49,000 comments, according to the July 7 

NIH’s final guidelines define hESCs as “cells that are derived from the inner cell mass of blastocyst stage human embryos, are capable of dividing without differentiating for a prolonged period in culture, and are known to develop into cells and tissues of the three primary germ layers. Although hESCs are derived from embryos, such stem cells are not themselves human embryos,” state the guidelines.

The guidelines also clarify the supporting documentation that must accompany requests for NIH funding for hESCs research. The institutes plan to issue additional guidance on how to implement the guidelines and how to manage pending applications, according to an 

. In the meantime, “ongoing NIH-supported research involving previously approved hESC lines may continue,” however, “no new uses of hESCs may be initiated in ongoing funded studies unless reviewed and approved by the NIH,” says the notice.

According to the final guidelines, hESCs that can be used should have been derived from human embryos:
     "1. That were created using 

 fertilization for reproductive purposes and were no longer needed for this purpose;
     2. That were donated by individuals who sought reproductive treatment (hereafter referred to as "donor(s)") and who gave voluntary written consent for the human embryos to be used for research purposes; and
      3. For which all of the following can be assured and documentation provided, such as consent forms, written policies, or other documentation, provided:
       a. All options available in the healthcare facility where treatment was sought pertaining to the embryos no longer needed for reproductive purposes were explained to the individual(s) who sought reproductive treatment;
       b. No payments, cash or in kind, were offered for the donated embryos;
       c. Policies and/or procedures were in place at the healthcare facility where the embryos were donated that neither consenting nor refusing to donate embryos for research would affect the quality of care provided to potential donor(s);
       d. There was a clear separation between the prospective donor(s)'s decision to create human embryos for reproductive purposes and the prospective donor(s)'s decision to donate human embryos for research purposes; and
       e. During the consent process, the donor(s) were informed…” in detail about the use of the cells and any research information obtained from the cells (more specific details are included in the final guidelines).

Applicants wishing to use hESCs that were derived from embryos before July 7, 2009, must meet the above requirements or must submit materials to a working group at NIH. The working group will make recommendations to the NIH Director, who will then decide on eligibility for NIH funding. Applications submitted to the working group still have to meet certain ethical requirements.
     
 An online NIH 

 will soon list hESCs that may be used in NIH-supported research. 

The National Institutes of Health (NIH) issued on July 7, 2009, final guidelines for human stem-cell research that widen the door to the cell lines that can be used if they meet certain ethical requirements.

Final Stem-Cell Research Rules Issued

Roche appears to want out of the Big Pharma crowd.  The company confirmed in a statement that it has officially withdrawn from the Pharmaceutical Research and Manufacturers Association (PhRMA) after being a member for 36 years. The withdrawal became effective June 30, 2009. 

The decision to leave PhRMA was largely influenced by Roche's move into the biotech sector following its acquisition of Genentech in March 2009. Genentech is a member of the Biotechnology Industry Organization (BIO). According to Roche’s public affairs office, "Genentech and Roche believe that BIO's purpose is closely aligned with the direction of the new company and, therefore, can represent the company's interests in Washington, among policymakers, legislators, and the general public."

At the same time, the company stated that it is “proud to have been a partner with PhRMA for 36 years in addressing critical issues affecting healthcare innovation, manufacturing, and investment and access to prescription medicines for US patients.” 

Roche also clarified that it is not severing its involvement with Rutgers University, despite some news reports that the company is pursuing such action. “Roche will continue to sponsor the Rutgers Pharmaceutical MBA program,” according to the company statement.

In related news, Roche is not renewing its membership with the Association of the British Pharmaceutical Industry (ABPI). The British association 

 Roche’s membership in July 2008 for 6 months after Roche reportedly breached the association's code of practice. The suspension was lifted in February 2009, but a 

 states that the British arm of Roche has decided for the time being not to rejoin ABPI. Roche has said, however, that it will continue to work within the association's code of practice, according to the 

This article was written by Stephanie Sutton, assistant editor at 

, with additional reporting by Angie Drakulich

Roche has officially withdrawn from the Pharmaceutical Research and Manufacturers Association (PhRMA) after being a member for 36 years.

Roche Pulls Out of Big Pharma

The US Food and Drug Administration has been sharing inspection information with its regulatory counterparts in the European Union and Australia since last July as part of a pilot program under the federal Interagency Working Group on Import Safety. Now, industry is forming an international pharmaceutical supply chain consortium known as Rx–360 to, among other objectives, create a shared program for auditing suppliers.   

The growing consortium is very similar to a model for third-party shared audits of active pharmaceutical ingredient suppliers run by the European Chemical Industry Council's Active Pharmaceutical Ingredients Committee.

But is industry really willing to join in the sharing game? We're all taught to share from an early age, but somewhere along the line, we get caught up in competition and slowly decrease our eagerness to confide in peers. Competition is important—it is the foundation of our economy—and in the field of science, intellectual property rights and company proprietary information require individuals to remain private about the details of their work. But perhaps this hiding of information has gone too far. There must be a way industry can learn to share without giving up all its trade secrets.

Consider this: To meet all the new requirements for securing the supply chain, industry would have to conduct 800,000 audits per year, said Rx-360's Martin Van Trieste at the June consortium launch meeting. Unless pharma firms are planning to go on a massive hiring spree—perhaps alleviating the US unemployment rate along the way—to conduct these audits, it may be time for industry to start sharing.  

The regulators are doing it. But industry's fear of sharing information may leave them behind.