China’s Cracking Down on Fake Vaccines, Plasma-Based Drugs

The Chinese government’s official news service reports that the nation is taking steps to secure its vaccine and plasma-based drug supplies.  By the end of last month, it’s FDA equivalent, the State Food and Drug Administration, had sent over 80 superisors to 33 plasma drug manufacturing facilities in 24 locations.  For more, read on.  If our FDA has a resource/workload problem, imagining what China’s must contend with just boggles the mind.  The brief also mentions that some of the raw materials for some plasma drugs had been “collected illegally.”

Grassley Probes Illegal Marketing of Lilly’s Zyprexa

From the Associated Press’ Matthew Perrone, word came today that Senator Charles Grassley had requested emails and other documents from Eli Lilly, after lawsuits suggested that the company had “downplayed risks” and “wrongly promoted” its top-selling drug schizophrenia and bipolar disorder drug, Zyprexa.

Company spokesman Phil Belt said the documents are a small fraction of the 15 million pages affected by the court order.

Click here to read the brief update from AP that appeared in Forbes.

PhRMA’s Response to “60 Minutes” and the Center for Public Integrity

There were few surprises in PhRMA’s response to the Center’s Report on Lobbying.  “It misses the mark when it comes to efforts by America’s pharmaceutical research companies to educate lawmakers,” said Ken Johnson, Senior Vice President. “Our priority has always been to help advance patient care and we have supported policies and programs that bolster patient access to safe and effective medicines,” he said.

But then how about the $19+ million in political contributions?

For more, read today’s balanced Los Angeles Times article.

FDA Inspections: Quality vs. Quantity; Is it Time to Remove the “F” from FDA?

By its own admission, FDA is doing fewer food and pharma inspections, a fact that Ed Silverman wrote about yesterday on Pharmalot. It seems a dangerous trend, and Representative Waxman first pointed it out last Summer, correlating it with drug quality and safety problems.

Maybe I’ve just drunk the FDA Kool-Aid, but, in a time where resources are dwindling,  I do believe in prioritizing risk and prioritizing inspections, so that those facilities that pose the greatest risk are inspected first. This is part of an overall FDA plan that makes sense and is showing positive results.

Why should one take a “traffic ticket” approach and assume that a large number of unecessary and poorly done inspections trumps a smaller number of risk-prioritized inspections?

But I think that it’s time for the Agency to “decouple” Food from its activities, so that it can focus on drugs, especially since that field is becoming so complex, and leave food inspections to the Department of Agriculture, or perhaps, as has been proposed, a separate Agency. 

Imagine a field inspector with a science degree (could be in Geology) inspecting the Fulton Fish Market in the morning, Novartis’ upstate facility in the afternoon, and a Massachusetts biopharmaceuticals plant the next day?  And also remember that, apart from the Inspectorate Training program, overall  continuing education and training budgets for  inspectors and reviewers have been cut at FDA for the past few years. 

Can anyone be expected to be “on top of” both food and pharma/biotech anymore? I don’t think it’s a question of laxity, but suggests a need for more funding from the government, more training, resources and focus.

Japan Opens the Gray Maze: Moves to Cut 2.5 Years Off Drug Approvals

Japan, the world’s second largest drug market, is taking steps to speed new drug approvals that would cut two and a half years off the time taken to approve new medicines. according to JPMDA’s chief executive Akira Miyajima.  The Agency will hire 240 new drug reviewers over the next three years, he says, a sizeable increase, since there are only 340 reviewers there today.  Good news for Lilly, Wyeth and other drug companies that have been investing heavily in a very challenging market, but also good for Japanese companies and consumers, who must typically wait years for drugs from the U.S. or Europe to reach them.  Here’s more from Bloomberg.

Dr. Ulrich Taglieber, formerly Merck’s regulatory affairs director, and others outside of Japan described the situation that used to exist in Japan—aggravated by language, social custom and convention— in an article we’d published last year. Click here to read it, and here to read a 2004 article on the subject by experts Jean-David Rafizadeh-Kabe and Robert Fike. 

Mechanical Calibration Gets the Nod for Dissolution Testing

Dissolution testing is extremely important to drug safety, but it is still somewhat imprecise and has become an area of controversy, but an inside source says that mechanical calibration (which had been questioned by industry traditionalists and by USP, which  viewed it as supplemental to, rather than a replacement for, existing methods) will soon be listed as an “industry consensus” method for validating dissolution testing equipment. Here, the relevant “working standard” that ASTM’s E-55 committee has been developing.

For links (some of which work) to recent and relevant articles, including a summary of dissolution science, check out this recent newsletter from Varian. Varian Dissolution update. Those of you who have subscriptions to Science Direct should have no difficulty retrieving full text.

Janet Woodcock’s Testimony on Follow-on Biologics; A Lab Scientist’s Toolkit

FDA’s CMO Janet Woodcock testified at the House of Representatives committee hearing, chaired by Representative Waxman, today, in a thorough presentation of the issues and nuances involved. Testimony at House Committee Hearing today.

An excerpt below

“Current technologies, such as peptide mapping, protein sequencing, and mass spectroscopy enable manufacturers to determine, with certainty, the amino acid sequence of a recombinant protein. However, the amino acid sequence is the most rudimentary characteristic of a protein. Conclusive analysis of other aspects of a protein’s structure requires much more sophisticated technologies and is fraught with uncertainties that are proportional to the size and complexity of the protein itself. Such complexities include: folding of the protein’s amino acid chain into highly organized structures, post-translational modification of the protein with a broad range of biochemical additions (e.g., glycosylation, acetylation, phosphorylation, etc.), and association of multiple protein molecules into aggregates. It is the combination of the protein’s amino acid sequence and its structural modifications that give a protein its unique functional characteristics. Therefore, the ability to predict the clinical comparability of two products depends on our understanding of the relationship between the structural characteristics of the protein and its function, as well as on our ability to demonstrate structural similarity between the follow-on protein and the reference product. Although this may be currently possible for some relatively simple protein products, technology is not yet sufficiently advanced to allow this type of comparison for more complex protein products.  Functional characterization, using in-vitro tests, is also of great importance in assessing the similarity of two proteins. For proteins with a well-understood mechanism of action and available functional assays, extensive functional comparisons will enhance understanding of comparability. Future scientific advances may facilitate the ability to perform more meaningful functional testing…

We asked BMS Senior Scientist Declan Moran who is working as part of a multidisciplinary research team in Ireland to develop new bioanalytical tools and methods, which existing commercial analytical technologies (besides the ubiquitous “MALDITOF” were becoming more important in helping to evaluate comparability of “followon” and original biogenerics, and he shared the following insights.

“…No single analytical method can be used to definitively assign comparibility. Orthogonal approaches are proving very useful, and “hyphenated MS solutions” offer 85-90% of the answers, although NMR would still be needed to confirm configuration. Recent advances in gene expression technologies will play a crucial role, since most biotherapeutics are hosted in parent cells(CHO being the favorite due to past FDA approvals), so separation of host cellular material from protein of interest is key and the presence of such things at mitochondrial DNA or RNA could be significant.

Array recognition technology is also becoming very effective in addressing issues, whether these are SPR based technologies such as Biacore or Lectin arrays, as patented by Procognia. All serve to build a fingerprint of the therapeutic of interest.

There is no getting away from traditional wet techniques sucha as IEF and SDS -PAGE as these are still best at separating isoforms.

But here is the rub. To truly say a follow on Biologic is the same as the original, the isoform fingerprint will have to be identical. Thus sensitivity now plays a key role. As yet no analytical methods can successfully map a full isoform sequence and therefore the isoform with the best half life and most bio availability may in reality only represent a very small proportion of the pattern in percentage mass terms. However if the FDA adopts a risk mitigation approach and determines the success of a follow on based upon its treatment affect and lack of immunogenicity than all is up for debate as they will be looking at patient response as the measure and not absolute comparibility.

If follow ons are allowed in the manner stated above then the big players will need to look very seriously into their R&D expenditure, as the cost to market will not support a challenge in the initial years of return on investment.

The key analytical methods shaping up in this area are:

MS- TOF,Q-TOF 3Q all with hyphenated capabilities

Array sequencing(SPR Lectin Ab specific)

qPCR

IEF SDS-PAGE

Any platform based around signal enhancement and sensitivity (whether optical or acoustinc); fluorescence is becoming a key indicator…”

Mytogen President Jonathan Dinsmore on Stem Cell Therapeutics for Heart Disease

Jonathan Dinsmore, President of Mytogen, Inc., discusses cell therapies that would regenerate heart tissue damaged after a heart attack or other problem.  The company has been given FDA approval to do additional clinical trials for efficacy.

Play Video

Mytogen President Jonathan Dinsmore on Stem-Cell-Based Cardio Therapies - Bloomberg Bloomberg - (BLOOM) Mar. 26, 2007. 08:48 AM EST

FDA’s CDER Gets New IT Director

FDA just appointed a new CIO a few weeks ago. Today, the Agency announced that it had appointed a new IT Director for CDER.  More on Jim Shugars, the new appointee, below.

We are very pleased to announce that Jim Shugars has agreed to serve as the Director for the Office of Information Technology, CDER (OIT-CDER). Jim will report to the FDA CIO and manage the IT staff that supports CDER. Jim has served as Acting Director for OIT-CDER for over a year. In the short period of time he has been acting in this position, he has proven to all in the Agency that he is the right person to lead CDER’s information technology towards the FDA wide approach. Jim works with a wide range of government and contract personnel in defining, developing, and implementing automated systems. He has provided management and executive oversight in developing the Structured Product Labeling program that established the standardized repository of drug labels at the National Library of Medicine and in the development of adverse event, electronic listing, and document management systems. As we developed the Document Archiving Reporting and Regulatory Tracking System to track Pre-Market drug application submissions, Jim’s executive oversight and team development was outstanding.

Jim has demonstrated the qualities necessary to be a very successful leader within the organization. He brings over 25 years experience as a Programmer, Systems Engineer, Program Manager, and Information Technology Executive including over fifteen years in management/supervisory positions with the FBI and the FDA. Jim has a Bachelor of Science in Mathematics from Frostburg State University.

Biogenerics, Take 2 : FDA’s Janet Woodcock to Testify at House Hearing Today

Following the recent Senate committee hearing on biogenerics/followon biologics, Representative Waxman and the House Oversight Committee will hold a hearing on the subject this morning; FDA’s chief medical officer Janet Woodcock will testify at that meeting, transcripts and videos of which will be available later. For more, click here.