As safety concerns regarding use of blockbuster human painkillers reignited in late 2004, so too did reform rhetoric surrounding approval and post-approval monitoring of drugs.
The issue? Preliminary results from studies are showing an increased risk of cardiovascular events in various situations to Vioxx, Celebrex, Bextra and the Cox-1 inhibitor Aleve. Throw in Food and Drug Administration (FDA) whistleblower David Graham, and the volume from critics is turned up on FDA reform.
In an exclusive interview with DVM Newsmagazine, Crawford talked about the most recent human drug and vaccine safety problems, his goals for FDA, user fees, balancing consumer safety with expeditious product approvals, his career and interactions with President Bush.
Crawford is no stranger to FDA, tough politics or congressional hearings.
He has worked with seven FDA commissioners during his career and has testified before Congress 134 times.
The veterinarian says the process is decidedly American.
It's a time when Congress questions government agencies about issues or practices — an important form of checks and balances.
"It is a serious matter that goes on. Some people say it's just theater. There are theatrical elements to it because you are trying to put your best foot forward as they are. But it is about the rebirthing of the Republic," Crawford says of congressional hearings. "Sometimes it feels like an appendectomy without anesthesia, but it's part of the job," he smiles.
"The system works. It doesn't look like it works sometimes either to the public or the people involved in the maelstrom, but it does work," he adds. "Without that freedom of expression, we would not be the country we are today."
For Crawford, the ordeal meant answering a blistering array of media and congressional inquiries in the aftermath of the flu vaccine shortage, which at times was described in news reports as nothing short of volatile. More gasoline was thrown on the political fire when studies questioned the safety of four leading human painkillers, starting with the recalled Vioxx. The consumer headlines taunt that FDA's approval policy "pits speed against safety," and that FDA has become "a pawn to big pharma."
Don't tell that to Crawford, who says FDA's mission hasn't wavered. It's always been about public health, and safety and security of drug products, he says.
Product safety/recalls As the lead regulatory body, FDA remains caught in the middle of a paradox. Consumers want safe, efficacious, and greater access to drugs. Pharmaceutical companies, after satisfying safety and efficacy requirements, want speedier reviews.
The stakes are enormous.
FDA is estimated at regulating product sales that top $1.7 trillion.
How does Crawford balance the two extremes?
Crawford explains, "Between 2 to 3 percent of all the drugs that FDA approves have to be taken off the market after they are approved. The public rightfully expects us to be fail-safe. If not fail-safe, then figure out some way of dealing with it."
It's a statistic that has held true for the last 30 years, he adds. "Whatever we do, we do not seem to have gotten control over that and neither do other western countries.
"The public wants something to happen when one of those drugs are pulled off the market, regardless of how long they have been on the market or how may people have been injured. They usually believe that we should have acted earlier, or the company should have acted earlier.
The public wants a very transparent peer-review policy, and they want to understand why FDA is making these decisions," he adds.
Consumers also demand greater access to information on adverse reactions, and the agency has responded by placing a great deal of information on its Web sites.
Crawford adds that consumers demand risk-management programs to minimize adverse reactions. In the next six months, FDA is planning an evaluation of these drugs through the help of the National Academy of Sciences.
"We do need an in-depth look by the world's leading scientists in this particular area."
In addition, FDA is conducting "an internal analysis to determine what the situation truly is."
"The 2 to 3 percent is (a statistic) we have testified before Congress many times, but the intricacies of why that is happening will be new to a lot of people," Crawford says. "We are putting forward an internal paper on that."
What will history say? Credited with championing Codex Alimentarius and USDA's Hazard Analysis Critical Control Point System (HAACP) for the Food Safety and Inspection Service, Crawford's vision for FDA is clear.
He wants to create a suite of modernization and enforcement processes that will last for the next 10 to 20 years.
The agenda is to advance good manufacturing practices (GMPs) among pharmaceutical companies and a risk-based approached to determining drug safety, dubbed the "critical path". Crawford explains this critical path concept is "how to use modern scientific techniques to get newly discovered drugs, vaccines, medical devices and laboratory tests to the bedside as quickly, expeditiously and predictably as possible." It is a major agenda item for the acting commissioner.
"It will be a calculus that doesn't look like a Republican or Democrat thing, it is just something that is a source of steady improvement over time at FDA. I think the critical-path approach will be around for the next 10 to 20 years."
FDA has advanced an agenda of modernizing GMPs for companies that included some fairly hefty fines for companies based on violations. Crawford says the agency pays particularly close attention to vaccine and medical product GMPs.
"It would be wrong to say I'm the father of any one of them, but during the time I'm here, those are going to be major accomplishments," he says.
This "critical path" report is a white paper that outlines key problems in review and development of novel drugs, which have been steadily declining. In the mid-'90s, FDA received 44 new molecular entities overall and 44 new biologic license applications a year. In the last fiscal year, FDA received 28 submissions for new molecular entities and 20 applications for new biologics. Of those new molecular entities, typically just a few are targeted to animal health.
This initiative, however, focuses on the decline of new drug development.
Crawford explained the trend to attendees of the Drug Information Association this fall: "But after a study of this problem, our agency identified as the major shortcoming the lack of scientific insight that are essential for translating an experimental substance into a safe and effective healthcare product. This is the crucial issue. In the FDA's view, the state of the applied sciences that are used for medical product development lags behind the striking advances in the basic sciences that can make medical breakthroughs possible. As a result, the drug development process is obscured by uncertainties that frequently culminate in unexpected obstacles and project failures — failures that could be avoided if the obstacles could be foreseen at the start of the development process."
What is lacking are predictive tools "including assays, standards, computer modeling techniques, biomarkers and validated surrogate endpoints for use in clinical trials — that would enable sponsors to separate promising candidates from probable failures early in development," he adds.
The report calls for sophisticated development tools in product safety (animal toxicology and clinical trials), efficacy and the product's potential for viable large-scale manufacture.
This agenda "will be developed with a lot of external help from the academic and research communities," Crawford explains.
"We also want people within FDA to have ownership in it," he says.
He successfully used the same principles at USDA's FSIS when he advanced the food safety regulatory tool HAACP. Developing ownership is key to its future success, Crawford adds. When HAACP was originally on the drafting boards, his special assistant immediately pulled together a 30-person team and sub-teams. Of the 10,000 people at FSIS, close to 1,000 people were in the planning and drafting stages.
That's what Crawford means by ownership. He left FSIS by the time HAACP received the recognition currently bestowed as a regulatory tool.
User fees There was a time in the 1980s, Crawford recalls, that saw far fewer products making their way through FDA to market.
"One year, we saw no new veterinary and only four human new molecular entities. If there was a person with a rare disease that could later be treated with some pharmaceutical or an animal population that need special therapy, they could forget it in the United States. It was a period of time that FDA was very conservative and afraid of being too cozy with the industry."
In 1993, human medicine adopted user fees as a mechanism to spur drug approvals. Congress has approved similar legislation for FDA's Center for Veterinary Medicine, dubbed the Animal Drug User Fee Act (ADUFA), which ultimately will allow CVM to hire 60 new people to review drugs.
Crawford says he originally was opposed to user fees because he thought they might be a conflict of interest, but he's a believer now. The concept gets money into FDA for specific review.
He says it also allows the agency to prepare for new chemicals coming through the research and development pipeline.
"We used to hear things about a new generation of antibiotics coming. But we didn't dare ask industry because that would be a conflict of interest. So we hung around here with the same old tired collection of personnel; there are too few of us and (we're) too inexperienced. And then along came this whole new set of drugs that we were not ready for, nor did we have expertise in. Now we sort of know what is coming, and we can plan for it. I think ADUFA and its descendants have been very good for FDA and good for the country."
Day in the life So what's a typical day like for an FDA commissioner?
Count on morning meetings with key staff to cover the day's agenda. Assignments are handed out, and the day's agenda is set. Many more meetings ensue. In fact, he says that half of any given day's meeting are internal, half external. He gives about one speech a day at some function. He does about 300 a year. He maintains two offices: one in Rockville, Md., and one near Capitol Hill. He is in both offices almost every day.
Due to his hectic schedule, Crawford rarely travels outside the beltway anymore. "The commissioner needs to be here," he explains.
By any standards, the 66-year-old veterinarian runs at a quick clip.
"It's almost like playing a sport. You have to take care of yourself — eat and sleep, and all of that. It takes conditioning to do it."
Crawford relies on speechwriters and staff to help him prepare.
"Now we have the controversy about the flu vaccine and the post-approval of drugs. It just gets enough newspaper and television attention that these both have. Everyone wants you to talk about the issue. If your speech isn't centered on the issue, then that's all the questions you will get. So, it sort of looks like you are evading the issue. Sometimes it is templated; sometimes it's extemporaneous."
What veterinarians should know For those wondering if Crawford's role at FDA also has elevated veterinary medicine in a positive way, the Auburn University veterinary graduate thinks it has.
"I have been able to run the place for a couple of years. If anyone thought a veterinarian couldn't do it, they are wrong."
He adds that the two veterinarians in the Senate have "elevated veterinary medicine a great deal." He's referring to Senators Wayne Allard and John Ensign.
"I don't think anyone has anything against veterinarians; they just don't think of them as doing this kind of thing. And yet, on the other hand, similarly trained professionals are expected to run this program or the other. I think this does advance veterinary medicine."
In the end, Crawford has one message for his colleagues: He hopes veterinarians will continue to have constructive involvement within CVM.
"They shouldn't think of FDA as the enemy. I think it ought to be a source of great pride to veterinarians that there is an entity in FDA that looks out after them, polices them and causes research to be done to help them and animals. Having an armamentarium of drugs is a magnificent thing. It has never been as good in any other country, and I've never been more proud of it."