Angie Drakulich was editorial director of Pharmaceutical Technology.

Angie Drakulich

The Senate confirmed late Monday night Dr. Margaret A. Hamburg, 53, to lead the US Food and Drug Administration. Her confirmation comes two months after President Obama nominated her for the job. Hamburg has served as New York City’s acting health commissioner, US Department of Health and Human Services (HHS) assistant secretary for planning and evaluation, and more recently, a senior scientist at Nuclear Threat Initiative (NTI). 

In a May 7, 2009, statement, US Senator Ted Kennedy (D-MA) described Dr. Hamburg as a “widely respected for her expertise in community health, bio-defense, and nuclear, biological, and chemical preparedness.” He went on to say that Dr. Hamburg “will face many challenges as FDA Commissioner, and she is obviously well-qualified to deal with them.” Swine flu, contaminated food products, and drug supply chains will be among her first challenges.

Hamburg’s confirmation, which was unanimous, completes the HHS food and drug leadership circle, with former Kansas Governor Kathleen Sebelius serving as new HHS Secretary and Joshua Sharfstein, former Baltimore health commissioner, serving as principal deputy commissioner of FDA. Hamburg will be sworn in as commissioner this week.

Obama’s Choice of Hamburg to Lead FDA: Good or Bad?

Articles

The Senate confirmed late Monday night Dr. Margaret A. Hamburg, 53, to lead the US Food and Drug Administration.

Hamburg to Take Hold of FDA

The European Medicines Agency (EMEA) recently issued for public comment draft procedures for evaluating advanced therapy medicinal products (ATMPs). The agency’s Committee for Medicinal Products for Human Use (CHMP) and its Committee for Advanced Therapies (CAT) adopted the procedures in late March 2009. CAT was established in 2007 to assess the quality, safety, and efficacy of ATMPs, which EMEA defines as “medicinal products for human use, and are based on gene therapy, somatic cell therapy, or tissue engineering,” according to the agency’s 

The draft procedures on ATMP evaluation specify the roles and responsibilities of two assessment teams involved in ATMP evaluations and outline a 246-day procedure between CAT and the applicant to conduct the full evaluation. For example, the applicant must provide responses to CAT questions on the 121st day of the evaluation and a final draft summary of the product on the 171st day. Upon approval-no later than day 215, according to the draft document-it is the applicant’s responsibility to submit information to EMEA.

Comments on the draft evaluation procedures are due July 6, 2009, and can be sent to 

CAT also recently issued procedural advice on the provision of scientific recommendation about the 

. Scientific recommendation is optional for applications, but the 60-day procedure is meant to determine whether a product based on genes, cells, or tissues meets the official definition of an ATMP so that related questions may be addressed before an applicant submits a marketing authorization application or other information to EMEA. Comments on the procedural advice document are due on June 8, 2009, to 

The European Medicines Agency (EMEA) recently issued for public comment draft procedures on the evaluation of advanced therapy medicinal product (ATMPs).

EMEA Releases Draft Advanced Therapy Medicinal Product Procedures

Just one year ago, in May 2008, the US Food and Drug Administration launched the Sentinel Initiative to transform the agency’s ability to track the safety of drugs, biologics, and medical devices once they reach the market. The national electronic system is meant to complement existing FDA systems for tracking adverse-event reports. The agency is now beginning to issue project reports about how to develop and implement the system, which will be completed in stages. The reports will be available on the agency’s Sentinel 

 and under docket number FDA-2009-N-0192. The first 

 discusses the evaluation of existing methods for safety signal identification.

  Ideally, the Sentinel system will allow FDA to “query large participating data sources quickly and securely for relevant product safety information,” according to an agency notice in the May 7, 2009, 

. “FDA would send questions to participating data holders, who in turn would, in accordance with existing privacy and security safeguards, evaluate their data and send summary results to FDA for agency review.” The system will facilitate the development of active surveillance methodologies related to signal detection, signal strengthening, and signal validation. Eight 

 have been awarded through the Sentinel Initiative to help in this process.

  The first contract project to be released identifies, describes, and evaluates signal-detection methods that could be used in the Sentinel program. The report analyzes the signal’s use for: postmarket surveillance; sensitivity, or ability to appropriately identify important safety signals; specificity, or ability to appropriately identify the absence of important safety signals; ability to minimize both false-positive and false-negative safety signals; robustness of the methodology to perform across different types of data systems for detection of different types of safety signals; flexibility of the methodology to adapt to different situations and to change thresholds for different safety issues as desired, and barriers that exist to using each identified methodology. 

  The goal of the report, according to the website, is to make further recommendations for signal-detection methods. Comments on the overall docket availability or project report can be submitted to the FDA Division of Dockets Management 

  For more on this topic, read these previous stories:

FDA's Sentinel Initiative Will Improve Adverse-Event Tracking

Sentinel to Transform Drug Development and Oversight

The first project report on FDA's Sentinel website, discusses the evaluation of existing methods for safety signal identification.

FDA Issues First Sentinel Initiative Project Report: Statistical Methods

As of May 7, 22 countries had reported 1516 cases of swine flu, according to the World Health Organization, and multiple companies and governments are working to make vaccines available to the population. 

 spoke with Rangappa Ramachandra, program director and lead scientist of immunology services at Covance, about what’s involved in developing and manufacturing a vaccine as the pandemic progresses.

 A comprehensive drug-development services company, Covance has been providing immunology services such as R&D and preclinical vaccine testing to pharmaceutical and biopharmaceutical companies since 2005.

What is known right now about the prevalent strain of virus? Have many different strains emerged yet, or are vaccine makers working to combat one strain? 

 The current flu outbreak in humans is caused by a novel H1N1 flu, commonly known as swine flu. There is one strain and no antigen drift [has been] reported in this virus until now. The US Centers for Disease Control and Prevention (CDC) are currently working to create the reference virus strain and it is [to be made] available to vaccine companies by the end of May for vaccine manufacturing. The new strain is a ressortment of four strains of influenza A virus (a new strain of H1N1). CDC reported that the four components include one strain from humans, one strain from birds, and two strains from swine.

What key risks and challenges are involved?

 After getting the reference virus strain from CDC, vaccine manufacturers [will] follow the technology that is very similar to seasonal and universal flu vaccine development. The pathology of this novel H1N1 virus is unusual in that it targets young individuals and causes severe lung pathology due to over-activation of the immune system and induction of cytokine storm. Key risks and challenges involve demonstrating the safety and efficacy of the vaccine without any pathology in the vaccine recipients.
We actually do not know the growing conditions of this virus, or how well this virus grows in eggs or in tissue culture…. Covance does, however, have excellent scientific expertise to start these studies in animal models quickly and efficiently to determine immunogenicity and the minimum dosage to induce optimum protection and safety.

  Other challenges include… making [the vaccines] available to control the pandemic. We will not have enough vaccines to protect the population. In addition, we do not have sufficient vaccine production capacity to make required vaccines to protect everybody. Although antivirals can meet the immediate needs, immunity is the best long-term solution. Currently, vaccines and their manufacturing are attracting increasing investment.

 Can you walk us briefly through the types of tests required to develop a pandemic flu vaccine and how the time crunch may affect those tests and their results? 

 The complete licensing application or dossier submission should contain administrative data, quality data, preclinical testing and clinical-trial data in accordance with FDA-CBER regulations and the European Directive. The first and foremost step in vaccine development is availability of the reference seed virus to manufacturers. Using current and novel technologies, manufacturers start growing the virus in bulk…. Once the bulk virus is available, the following steps occur: 

 The final drug substance and drug product should be sterile and [include] bulk-containing purified virus surface antigens. The final product should contain only haemaglutinin (HA) and neuraminidase (NA) antigens. A detailed manufacturing process and process control should contain: virus propagation, virus purification and antigen preparation, specification and characterization, batch analysis, bulk- and storage-vessel conditions. Once the drug product preparation is completed, both drug product and finished fill product should be tested for stability.

 The inactivated (killed) purified product, with or without adjuvant, should undergo preclinical testing designed to demonstrate the immunogenicity in mice, rabbits, and ferrets. The efficacy of the vaccine should be demonstrated in a ferret model by challenge exposure. In addition, the vaccine will need to be tested for lack of abnormal immunotoxicity in mouse and guinea pig models. For all adjuvanted or nonadjuvanted vaccines, lack of local or systemic toxicity should be demonstrated in rabbits. Because this virus is known to cause severe lung pathology due to stimulation of robust immune response and cytokine storm, it therefore may be required to show a lack of systemic toxicity in vaccinated animals.

  These are the minimum preclinical vaccine testing requirements for initiating a Phase I clinical trial. They should be thoroughly planned and executed timely to complete all the preclinical studies. There is no fast track during the preclinical vaccine testing stage (particularly for safety and immunogenicity). Instead, to save time, the above studies need to start simultaneously. This takes proper planning of resources, facilities, technical personal, and contingency planning. And finally, FDA’s CBER will then need to review any IND application under its fast-track guidelines to avoid delay in licensing or releasing the vaccine for public use.

In the case of this flu, what type of immune response is optimal? 

 In general in viral infections, to induce complete protection, we need both humoral (HI) and cell-mediated immune (CMI) responses. A majority of the nonadjuvanted vaccines have a suboptimal efficacy profile, and tend to induce only humoral antibody response against influenza strain, with very low or no cytotoxic T-cell response. Therefore, use of novel adjuvants that induce both B-cell and T-cell in the vaccine formulation is critical to HI and CMI responses for complete protection. The efficacious vaccine should induce sterilization and long-lasting immunity. 

Are there any particular technologies or techniques that enable the rapid development of a vaccine? Is the vaccine developed in eggs, or cells? Is it a live attenuated vaccine or a killed vaccine? A recombinant vaccine? 

 Creation of a live attenuated virus is a time-consuming and laborious procedure. Qualification of such live vaccine reference strains per regulatory guidelines takes a long time (1 to 2 years). Therefore, the vaccine should contain a killed (inactivated) virus (either propagated in eggs or cells) or a recombinant vaccine…. [Because] there are several biotechnology companies actively involved in the development of universal vaccines using recombinant technology, [that] technology may play a major role in the development of efficacious vaccine for this new flu virus H1N1.  

Some reports say we may have a swine flu vaccine in six weeks. What is your best estimate regarding the timetable for a vaccine? 

 Here we are not talking about a small batch of vaccine; we need millions of doses for the national stockpile to protect the human population. Six weeks is an unrealistic number. In my best estimate, it takes about 8 to 10 months, if vaccine R&D, manufacturing, and final batch release is done as planned.

Once a vaccine is produced, how can we be sure of its safety and effectiveness? Looking ahead, how do you create (or attempt to create) a vaccine that covers most of the current strains as well as those likely to arise? 

 That is a real risk in the flu vaccine business…. During passage from human to human, this virus may lose virulence, adapt to humans and not cause any disease. On the other hand, during serial passages in humans, the virus may gain more virulence and become highly pathogenic. In either instance, the virus retains its original anatomy; therefore, vaccines produced against the original wild type, novel H1N1, will still work against high and low virulent viruses.

  The development of traditional vaccines against flu viruses is always risky due to constant antigen drift and ressortment of the virus in nature. Vaccine candidate antigens, namely haemaglutinin (HA) protein, are highly unstable and prone for drift. The only solution to create a stable universal vaccine is to use highly conserved proteins of the virus such as M2e protein or internal proteins. These proteins are present in low numbers and do not play a major role in viral replication and pathogenesis. One of the weaknesses of the M2e protein is that it is a poor immunogen and does not induce a robust immune response. But its immunogenicity and antigenicity can be increased with novel adjuvants. 

  Such universal vaccines will be highly effective against most seasonal strains as well as new strains. The beauty of such vaccines is that they can be manufactured any time of the year and vaccine companies need not wait for CDC to release reference vaccine flu strains each year. 

What has Covance learned through its experiences thus far when it comes to developing complex vaccines? 

 Vaccine development is a complex process and heavily regulated by several agencies because of the nature of its use in healthy populations…. The most important [deliverable] is timely execution of studies…. Vaccine developers are [also] demanding: 

More flexibility and [the ability to] to focus on       innovation and internal core competencies 

The ability to meet rigorous regulatory compliance       (national and international)

Functions that can be readily outsourced to a       competent partner including all investigational new drug (IND) enabling       studies (e.g., animal model development, safety and efficacy,       immunotoxicity and immunogenicity, dose response, and stability and       potency). 

In what ways is Covance helping to develop a swine flu vaccine at this time? 

 Covance Immunology and Preclinical and Clinical Vaccine testing services are uniquely qualified to design and integrate complex projects with cutting-edge technology, helping to make a quick decision on the success of the project…. Our vaccine testing methodology is based on sound scientific expertise, rapid study start, multispecies experience, state-of-the art facilities, study design development, testing, execution, and reporting, all of which are unique for the success of the project. The Covance niche is its scientists-they have extensive experience in veterinary medicine, vaccinology, immunology, infectious diseases, and immunopathology, in order to deal with complex projects.  Our solutions help move one phase of vaccine development to the next to save money and allow instantaneous use of information and technology. 

Covance provides operational service and scientific excellence for the execution of studies required for flu vaccine testing, including:

 Discovery studies (animal model development for proof-of-concept efficacy studies for influenza vaccines and adaptation of influenza virus to a mouse model)

 Clinical-trial studies in animals (these studies mimic the studies in animal models by, for example, mixing antigen and adjuvant prior to injection)

 Specific pre-IND and IND enabling studies for flu vaccine (

  Several vaccine pharmaceutical and biotech companies have approached Covance Immunology Services for vaccine preclinical testing in animal models (mice, rabbits, and ferrets) to evaluate immunogenicity, dose response, safety/immunotoxicity, and potency of the novel H1N1 vaccines.

Read a related blog post on PharmTech Talk titled "

Vaccines Progress Along the Critical Path

" by Maribel Rios, and also read her news story "

Covance talks about the risks, challenges, and tests required to develop a pandemic vaccine.

How to Make a Swine Flu Vaccine

The US Food and Drug Administration issued a 

Label Comprehension Studies for Nonprescription Drug Products

. The document provides guidance on the design of label comprehension studies. These studies are used to assess the extent to which consumers understand and apply information on nonprescription drug labels.

The draft guidance incorporates comments from a September 2006 meeting of the Nonprescription Drug Advisory Committee regarding the analysis and interpretation of consumer behavior studies as tied to nonprescription drugs.

Comments on the draft guidance can be submitted electronically at www.regulations.gov. Comments are due July 30, 2009.

 on Apr. 28, 2009, that requires manufacturers of over-the-counter (OTC) pain relievers and fever reducers to include warnings about potential safety risks in their labeling. The rule applies to acetaminophen and nonsteroidal anti-inflammatory drugs such as aspirin, ibuprofen, naproxen, and ketoprofen. Manufacturers must prominently display the active ingredients of these types of drugs on both packages and bottles. 

, exceeding the dosage recommendation of acetaminophen as well as alcohol use with acetaminophen can increase the risks for severe liver damage. With nonsteroidal anti-inflammatory drugs, the risk of stomach bleeding may increase in those individuals also taking blood thinners or who exceed nonsteroidal anti-inflammatory dosage. Alcohol use is a concern with nonsteroidal anti-inflammatories as well.

  Revised labeling must include the risks of stomach bleeding for nonsteroidal anti-inflammatories and severe liver damage for acetaminophen, according to the final rule. In addition, drugs containing acetaminophen must include a warning on the label that instructs consumers to check with their doctor before they take the blood-thinning drug warfarin.

  The risks associated with the use of these products “need to be clearly identified on the label so that consumers taking these drugs are fully aware of the potential harm they can cause,” said Charles Ganley, M.D., director, FDA’s Office of Nonprescription Drugs in the Center for Drug Evaluation and Research, in an FDA release. 

  The final rule calls for manufacturers to revise product labels by May 28, 2010. 


The US Food and Drug Administration issued a draft guidance for industry, Label Comprehension Studies for Nonprescription Drug Products, in the May 1 Federal Register.

FDA Issues Draft Guidance on Label Comprehension Studies and Calls for Revision to OTC Labels

Global market research firm IMS Health issued a disappointing 

 last week regarding the state of the pharmaceutical market. The world pharmaceutical market is now forecast to grow 2.5–3.5% this year to $750 billion, two percentage points lower than predicted last fall (which called for an estimated $820 billion), according to an IMS Health release. US pharmaceutical sales are likely to drop by 1–2% in 2009 with an essentially flat five-year compound annual growth rate (CAGR), while other developed markets (Japan, France, Germany, Italy, Spain, Canada, and the United Kingdom) will experience a CAGR of 1–4% during the next five years. The worldwide financial crisis is the primary culprit. 

Looking ahead, IMS predicts a rebound in 2010, but even then, expiring patents in 2011 and 2012 may curb sales growth, according to the release. As a result, the expected global CAGR for the pharmaceutical market through 2013 is 3–6%.

There is better news for the pharmerging markets (Brazil, Russia, India, China, Mexico, South Korea, and Turkey). IMS predicts that these countries’ pharmaceutical markets will grow 13–16% through 2013, ultimately contributing “more than half of the global market’s growth in 2009 and sustaining an average 40% contribution through 2013.”

Where should developed countries turn next to keep their pharmaceutical markets strong? IMS points to innovative treatments in biologics and new chemicals, and especially specialty products. There are potentially 6–10 new blockbusters to be launched this year and in 2010, reports the firm.

Global market research firm IMS Health issued a disappointing report last week regarding the state of the pharmaceutical market.