They say that change is about the only constant in life (we’ll leave out death and taxes for the sake of this discussion).

And we all got an excellent reminder of that earlier this month when the FDA smacked Boston Scientific by saying the agency would not speed up the review of manufacturing changes required for Boston Scientific to resume selling its implantable heart defibrillators.

 As first reported by The Wall Street Journal, the medical-device maker recalled all seven brands of its defibrillators in March after having failed to receive FDA approval for the manufacturing changes. The company had earlier told physicians that it expected the review to take less time than the typical 30 days, according to the WSJ.

 Boston Scientific submitted the changes to the FDA for approval on March 15 and 16, according to an email sent by a Boston Scientific sales representative to a physician on March 17 that was reviewed by WSJ.

What’s at the core of Boston Scientifics’ problem here? Well, at least part of it is change control failures. As noted in the Journal report, “The Natick, Mass., company’s failure to report the manufacturing changes to the FDA was the latest in a string of problems in following reporting requirements. The FDA is investigating the company’s failure in this recent case as well as past lapses,” an FDA official said.

But Boston Scientific is by no means the only company out there with a shaky hand on change controls. If you are reading this blog and your gut is starting to churn a little, you know who you are.

It may be time to review your change control program, right?

We thought it might help a little to review exactly what change control is, while we’re at it.

Good old Wikipedia defines change control within Quality management systems (QMS) and Information Technology (IT) systems as “a formal process used to ensure that changes to a product or system are introduced in a controlled and coordinated manner. It reduces the possibility that unnecessary changes will be introduced to a system without forethought, introducing faults into the system or undoing changes made by other users of software. The goals of a change control procedure usually include minimal disruption to services, reduction in back-out activities, and cost-effective utilization of resources involved in implementing change.”

And that’s a great definition — as far as it goes. What it leaves out is what can go wrong when change control isn’t handled properly.

But we already know what the consequences are when change control isn’t properly managed, don’t we?

ADDITIONAL RESOURCES

For more on the FDA’s change control requirements, go here:

Boston Scientific sees it all a little bit differently. In a March 18 release the company notes that the FDA did recommend approval of an expanded indication of its heart medical devices. However, Boston Scientific has thus far declined to address the FDA’s decision not to review it more quickly.

AssurX will host a complimentary webinar on this important topic April 8, 2010 at 10am PDT. Click here to register.

Gotta give the FDA some credit here. In addition to its transparency initiative we’ve talk about before, the agency is also trying to remove some of the mystery about how it handles inspections and other inner workings at the FDA. From where I sit, it appears to be a sincere effort and I believe it is helping outsiders better understand what the FDA is trying to do – and how it is trying to do it.

For example, at the second in a new series of monthly online webinars, FDA’s Michael C. Rogers, deputy director, Office of Regional Operations, said today (March 25, 2010)  tried to outline how an FDA inspection tends to work, and what drives inspectors before, during and after an inspection.

As an aside, Rogers also said that the agency currently has about 1,800 total inspectors across its full portfolio, though food gets the bulk of the bodies. He also said there will be more foreign inspections this year, and that the number should continue to grow.

Inspections are based on risk, Rogers said. In other words, the riskier the potential drug, device or food item, the more likely they will be inspected.

Most inspections are unannounced, Rogers said. Before they go on-site, the inspector on inspection team will look at previous inspection reports and identify what corrective actions were promised during prior inspections. They also prepare inspection tool kits with sampling equipment, info to drive inspection based on guidance documents and the Investigation Operations Manual. They also carry a camera to document evidence.

They also conduct “for cause” inspections driven by consumer complaints or other outside activity.

Typically, the inspection begins with a discussion with management to explain the purpose of the inspection, and they try to learn about the corporate structure and any changes made since last inspection. They also ask about complaints, positive tests or returns. Answers to those questions help FDA inspectors focus their on-site efforts.

Next, they go to the physical manufacturing area. They try to observe and understand the on-site process. They ask about acceptance criteria and want specifics on failures, especially the reasons.

Inspectors also draw a diagram of the facility showing the manufacturing process from start to finish. They’re looking for problems in the system and looking to identify critical control points in the manufacturing process.

FDA inspectors then identify procedures in place and assess if company is actually following them. They also look for controls in place to mitigate any contaminated products.

They also look at training and cleaning programs. They also watch employees while they are actually making the product.

If they find evidence of an adulterated product, they collect evidence based on inspector observations and collect samples to prepare their case for possible legal action in court.

At conclusion of inspection, the FDA team meets again with management. They then inform the top company official what is in the official Form 483. That form documents observations during the inspection but does not include final recommendations. They also ask for the firms corrective actions planned or in place to get into compliance.

These corrective actions are taken into account as agency formulates official recommendations.

After the inspection at the firm, the inspector develops a report back at the home office. It includes evidence collected and what the firm has already agreed to do about any shortcomings.

In some cases firms can offer voluntary corrections. But sometimes the agency decides it needs enforcement action such as a warning letter, and can also impose civil and/or monetary penalties.

The webinar was extremely popular. In fact, it “sold out” so many who tried to join it could not get in to the live event. There will be a recording available on Monday March 29.

UPDATE: Slides are now available from this event here in PDF format.

The past several months have brought forth numerous bits of news, pronouncements, expressions of concern and general uncertainty about the device regulatory regime, but also about FDA’s regulatory paradigm in general.  The recent piece in the New York Times regarding disagreement about the diabetes drug Avandia and the controversy involving accusations of conflict of interest by CDER head Janet Woodcock in the consideration of competing applications for enoxaperin, in the wake of last year’s resignation of Dan Schultz at CDER has led many to wonder where FDA is going under Dr. Margaret Hamburg.

Clearly, the new leadership at FDA is now acutely aware of the number and scale of the issues confronting FDA.  In their overwhelming majority, the scientists and technical specialists at FDA are dedicated and committed individuals.  At the higher levels, however, FDA has suffered from a series of problems, none more troubling in its long-term implications for the future of the industries it regulates, than its absence of imagination.

The FDA’s approach to science is rooted in statistical models, and those models and the people who analyze their results are wholly unwilling (as a matter of culture) to do finely tuned, meaningful risk-benefit analysis.  Several years ago, FDA’s own internal assessment cautioned that this blind reliance on statistical analysis will render it entirely incapable of assessing a new generation of complex devices, medications and combinations. The FDA is earning a reputation for inability to approve a product either safely or accurately, because it evaluates products in a statistical vacuum, without regard to societal benefit, need or even real-world safety variables.

There is some hope to be found in the fact that CDRH recently admitted that it needed new methods and new thinking, precisely along these lines.  That represents a refreshing start, but it will only make a difference if it is inculcated in FDA’s culture as a whole. Dr. Hamburg has quite a challenge ahead of her.

Mark Mansour is a partner in the firm, Bryan Cave, LLP

The early part of the 21st century was a tough time for the FDA. Its budget was curtailed, it lost some important personnel, and the word “acting” kept appearing on people’s business cards.

But 2009 just might be going down in history as the Year of the FDA Turnaround.

In October, the agency announced a long-overdue hiring binge that signals an even stronger FDA is on tap for 2010.

Watch for the agency to get a bigger budget in the coming years – though much of that emphasis will be on the food side and perhaps less on the drug and device side. For FY 2010, the FDA requested a total budget of $3.2 billion. This amount is $511 million more than FY 2009 and represents a 19 percent increase — the largest ever in FDA history. They won’t get it all, but they’ll probably come close.

Here are some other FDA highlights in a big year:

FDA Finally Gets Tobacco

It took years of lobbying and a new President, but in June 2009 the FDA was given the power to regulate tobacco products. This is a huge victory for the agency. It remains to be seen how the FDA will use this new power, but its surge of activity in the second half of 2009 suggests they want to seize the initiative.

Lawrence Deyton, M.S.P.H., M.D., joined the U.S. Food and Drug Administration (FDA) on Sept. 14, 2009, as director of the agency’s new Center for Tobacco Products. He hit the ground running.

“Our objective is to use the best available science to develop and put into action effective public health strategies to reduce the enormous toll of illness and death caused by tobacco products,” Deyton said .

Deyton was also asked how the tobacco regulation differs from FDA’s regulation of drugs or medical devices?

“FDA’s regulatory role for drugs and medical devices is usually based on a safety and effectiveness standard. The tobacco act establishes a new standard: to regulate tobacco products based on a public health and population health standard.

Deyton noted that when FDA gets an application for a new drug to treat a disease, the agency normally considers studies of patients who have the disease. ”But when we get an application for a new tobacco product, the law tells us we have to consider whether permitting the product’s marketing protects the public health and we have to evaluate the effects of the product on the population as a whole. We’re directed to consider both users and nonusers, and whether our action might encourage people who don’t use tobacco products to begin using them, or encourage people who might otherwise quit to continue using them.”

Bottom-line: It was a huge turf battle victory for the FDA and increases the agency’s overall regulatory clout.

Risk Communications

The agency also took big strides forward in how it gets the word out to industry and the public regarding risk. In its Strategic Plan the agency spelled out its perceived role in communicating the risks of regulated product use, defining risk communication anew for a 21st century in which evolving technologies have enabled increased patient and consumer involvement in managing their health and well-being. The document defines the three key areas (science, capacity, and policy) in which strategic actions, in collaboration with relevant domestic and international stakeholders, can improve the generation, dissemination, and regulation of risk communication about regulated products. It also identifies and details 14 specific strategies.

“FDA is showing its commitment to the goals of the plan not just by identifying the strategies it will implement, but also by identifying over 70 actions the agency plans to take within the next few years to improve risk communication,” it says in the Strategic Plan. The document also identifies 14 of those actions that FDA plans to accomplish within the next 12 months.

Clearing Up Transparency

Echoing an Obama campaign promise to make government more open and accountable to taxpayers, the FDA also walked the walked and talked the talk with its new “transparency”  initiative with public meetings in June and November. The agency also opened a blog that, so far, has had a fair amount of uncensored comment both pro and con about agency performance.

Here (Finally) Comes the eMDR Guidance

In August, the FDA unveiled their proposed guidance for ultimately mandating electronic submission of mandatory adverse event reports. It took a long time to come to fruition, and some are lobbying the agency to push it back another year or two, but the simple fact that it was released was a big deal in 2009.

Guidance on Presenting Risk Info

Before unveiling the eMDR rule, the agency also issued  in May the important draft Guidance for Industry: Presenting Risk Information in Prescription Drug and Medical Device Promotion. The guidance is important on several levels, but perhaps the most important is that it addresses factors the FDA considers when evaluating ads and promotional labeling for prescription drugs, ads for restricted medical devices, and promotional labeling for all medical devices for their compliance with the Federal Food, Drug, and Cosmetic Act and relevant regulations.

In doing so, it cleared up a lot of confusion in the industry and signaled a revitalized FDA that was on the way back.

Putting The ‘Food’ Back In Food & Drug Administration

Responding in part to pressure from Congress and consumer groups over beef and other food contamination recalls, the FDA also revitalized its food enforcement in 2009, and this is also an area where the smart money says they’ll be even more active in 2010. In September, the agency capped a number of new food initiatives by unveiling a new reporting system that gives the agency new enforcement teeth when it comes to the food chain.

Here’s a prediction: FDA historians of the future are probably going to see 2009 as the year the agency picked itself up off the ground and started to flex its regulatory muscle again.

FDA Uses Risk-Based Approach to Select Sites for Inspection

Leslie Ball, director of the Division of Scientific Investigations at CDER, has stated that the FDA is following a risk-based approach to selecting clinical trial sites to inspect. Ball also noted that the FDA is taking additional steps, including requesting third-party audits of representative samples of sites for a given study to compare with sponsor-monitoring reports and agency inspection results.

FDA Ratchets Up Overseas Inspections For FY 2010

The FDA has stated that it expects to increase its oversight of overseas pharmaceutical company activities by one-third in fiscal 2010, and double its total number of foreign inspections. Foreign drug facility inspections would increase to 924, up from just under 600 in FY ’09. The projected number of biologics inspections is 43.

SOCMA Calls for Combined Risk-Ranking

The Society of Chemical Manufacturers and Affiliates has called on the FDA to use combined risk-ranking for domestic and foreign food and drug manufacturers, stating that FDA refusal to combine risk-ranks puts U.S. firms at a disadvantage.

Warning Letters

The FDA has issued a warning letter to Procter & Gamble notifying the company that its Vicks DayQuil Plus Vitamin C and Vicks Nyquil Plus Vitamin C are illegally marketed combinations of drug ingredients and a dietary ingredient.

Recalls

The FDA and Cordis are notifying healthcare professionals of a nationwide recall of all lots of the CROSSOVER Sheath Introducer due to stretching or fracture of the sheath during use.

Pointe Scientific and FDA are notifying healthcare professionals of a nationwide recall of all size kits of Liquid Glucose Hexokinase Reagent catalog number G7517.

FDA Questions Role of Payments in Zimmer Study

Federal health officials have stated that an implant from Zimmer Holdings Inc. appears to be effective in treating spinal problems, but that they question whether company payments to physicians conducting the trial may have influenced the results.

Mark Mansour is a partner in the firm, Bryan Cave, LLP