Obama, McCain and the US FDA

It's election time in the US, when legislative activity moves “from theatre to circus with not much substance in between”. That’s the view of former US Food and Drug Administration commissioner Dr Lester Crawford, and he should know, having worked in this most powerful health agency on and off for 30 years.

In that time, he has first-hand knowledge of - to Australian eyes - the remarkable levels of scrutiny and criticism it comes under.

Crawford served under five different presidents – he managed to avoid the Nixon administration, and he’s pleased he did, he says - observing in that time the Democrat majority in the 1980s fall to the Republican revolution in the 1990s, and back to a Democrat majority in 2006 and how these political changes affected the functioning of the FDA.

He also observed the position of the commissioner of the FDA, the most powerful role in global healthcare outside the head of the World Health Organisation, become politicised, candidates for the job being nominated by the president and confirmed by the Senate.

In the past, confirmation was a painful enough process of up to four months. Now, it is up to two years.

“That happened in the Clinton administration and in the Bush administration,” he says. “That is also a period were it is very hard to get things moving and done.

“This will be the worst year for FDA in four years – actually in eight. We’ll just have to tough it out.”

Crawford, who was in Australia recently as a guest of Pricewaterhouse Coopers and QRxPharma, warns that approvals by the FDA will slow dramatically this year and into the next. The current leadership will bow out with President Bush, and the new president will probably not be in a great hurry to appoint a new one.

He doesn’t know Barack Obama well but has been on the receiving end of John McCain’s famous temper. Either way, things will not be the same, he says.

“I believe if the Democrats return to the White House, which people are predicting, you can pick out what FDA’s trend would be based on what’s happened since the Democrats took over Congress (in 2006),” he says. “That would be more regulation, in a nutshell.”

He is a little less sure of the alternative’s direction, but says McCain has never been impressed with the FDA.

“He has always, essentially since day one, thought that we did our job in not as efficient a way as he would like us to do it. He has sponsored some very constructive legislation and also fathered some resolutions in the Congress, which have tended to strengthen the FDA, but he would be a very strong critic of the FDA.

“I think there would be a period of time when there would be major changes and shifts in personnel. That may or may not be the case with Obama.”

Crawford himself was Bush’s nomination for the post of commissioner and had to undergo the griller that is a Senate confirmation hearing. He was deputy commissioner from 2002 and was nominated for the top role in February 2005.

He was confirmed in July 2005, despite some senators threatening to withhold confirmation following questions as to why the FDA delayed allowing Plan B, an emergency contraceptive, to be sold over the counter despite the agency’s own advisory panel recommending it do so.

In September of that year, just two months after his confirmation, Crawford abruptly resigned, saying he was tiring of the job and denying the decision had anything to do with financial irregularities.

He was later charged with conflict of interest and falsely reporting that he had disposed of or did not own stocks in companies the FDA regulates. He pleaded guilty to the charge, was put on probation and fined $90,000.

While his conviction has tarnished his record, and his small but regular donations to the Republican party put his comments about Obama and other Democrat senators, including Hilary Clinton and Ted Kennedy (see page 3 and 4), into perspective, he is quite certain about how the election will affect the functioning of the FDA in the short term.

According to Crawford, in an election year FDA activity essentially shuts down from July 1. The election is held on the first Tuesday in November and the new president is inaugurated on January 20.

In the transition time, a caretaker cabinet takes care of organisations like the FDA. “It’s a quiet time, or a dead time,” he says.

“After the inauguration, there is still a period of malaise because it is a long period of trying to find new leadership of the FDA. It is not remotely possible that the present leadership would continue, with either president.”

---PB--- FDA on autopilot

While the FDA is in autopilot mode, it may give overseas drug and medical device companies time to digest the ramifications of new legislation enacted earlier this year, called the Food and Drug Administration Amendment Act (FDAAA). This act has four different requirements that will affect both registered and candidate drugs and the clinical trials process.

“This Act started out to be a tying up of loose ends in legislation, but that quickly dissipated, because Congress saw it as an opportunity to add pet projects,” Crawford says. “All the projects that got through and were memorialised in the bill were Democrat-approved projects. Some of them had bipartisan support but not many.”

The first requirement, or the marquee item of the FDAAA as Crawford puts it, is the Risk Evaluation and Mitigation System (REMS). This is an extensive management plan for drugs that have adverse reactions, especially unexpected deaths, after they have been approved.

“When I was in charge there I saw these as something that you could do in order to get a drug back on the market, so risk management plans were used for Lotronex, the irritable bowel syndrome drug that was taken off the market because of adverse reactions. The risk management plan of that drug presaged what was to come and was a forerunner of this law.”

The most recent example is Tysabri, for progressive multifocal leukoencephalopathy, which had to been withdrawn temporarily from the market and then reissued with a REMS. Only a doctor trained specifically in the side effects will be able to prescribe these drugs, and must submit a patient medical report every month.

“Congress took note of that and now this system is in place with only 16 drugs on it at the moment but FDA has indicated to a number of companies that they need to submit a REMS by October of this year and those drugs are 11 in number, so there will be about 27 in total.

“The new drugs that are added will be joining things like thalidomide and Lotronex and others. Other companies have been contacted by FDA and asked to submit a narrative of why those shouldn’t have a REMS plan for their drug. This is going to change things a bit.”

The second item is that Phase IV has now been enshrined in the drug approval process. Under the law, the FDA can demand that Phase IV, the post-approval surveillance period, will become a requirement.

“I believe they will demand it universally in new chemical entities,” Crawford says. “And there will be the inevitable re-evaluation of those drugs that are already on the market.”

What this law will do is shift resources from the pre-approval process to the post-approval process, with the FDA spending much more time and resources on post-approval monitoring rather than its traditional role of ensuring safety and efficacy, Crawford says.

“We have to get ready for that and realise that this is the time for post-marketing surveillance, and we have to turn that phase into a science. There has to be a body of literature developed in the scientific world, universities have to form institutes for Phase IV … and we need to get this thing moving, or else it will be so ad hoc that there is going to be an embarrassment, or more importantly, a delay.”

---PB--- Paediatric labelling and clinical trials

The third new measure in the bill is paediatric labelling, in which all drugs, except those obviously not intended for children such as an Alzheimer’s drug, must have a paediatric indication.

This is a measure long championed by Hillary Clinton and was the substance of the first bill she introduced after becoming a senator, the Better Pharmaceuticals for Children Act.

“She was concerned – and all of Congress was concerned, because she was – with the fact that physicians routinely said that when they dosed a child with an adult preparation they simply halved it or [quartered] it and did that with a knife on the capsule or other absurdities.

“That attracted the ire of particularly the women’s movement in the US, which is a powerful movement. Now, the presumption is that before you put the drug on the market you will satisfy FDA that you have paediatric labelling for the drug.”

Waivers will be available for drugs that are not for use in children but regulations governing these waivers have not yet been issued, Crawford says. What it will do, he says, is add another layer of expense to the drug approval process.

“General drugs like antibiotics will all have to have the paediatric label and it will have to be based on trials or something that substitutes for trials like the scientific literature.”

And finally, in what Crawford calls the most sweeping and draconian change, is that all clinical trials must register with an FDA-approved clinical trial registry. Previously, clinical trials could be registered with entities such as the National Institutes of Health, but now it must be the FDA.

“If you are doing clinical research on a drug that is intended for FDA approval, including those that have INDs, you will have to register with an FDA-operated clinical trials registry,” Crawford says.

“It can’t be outsourced, it can’t be NIH, it can’t be university – it has to be FDA. For failure to do that, the penalties are abhorrent – you would be debarred from putting that drug through and if convicted you would be debarred permanently from the US market.”

In what will come as a revolution to the 102-year-old institution, for the first time the FDA will open overseas offices, expected to total eight in this fiscal year. While there has been no public announcement as yet, it is expected that three will be opened in China and two in India, with others in South America and northern Africa, Crawford says.

“This is going to change the face of the FDA, because … it has never had an international office, not even an attaché to the WHO or connected to the EU,” he says.

He expects that in time the offices will carry out inspections of manufacturing facilities and other regulatory oversight.

“I think it is going to change a lot of things and will make FDA more international-minded and it will help to deal with the current insoluble problem of the American consumer’s confidence in China. Any product with a Chinese identifier on it, whatever it is, right now is subject to great suspicion and it is not going well.”

According to Crawford, the contaminated pet food scandal of last year was the biggest incident ever seen by the FDA, with more hits on the FDA hotline registered than anything before.

“Then there was lead in toys and the last straw was the heparin incident. I think it is fortuitous that they are putting these offices in China – I’m not sure why they need three but there must be a good reason for it. They will make the public feel a little better about it.”

---PB--- Understanding the FDA

For his Australian audience, Crawford advised that if the local industry wants to know better what the future holds in the short-term, to consult the legislation on the FDA and Congressional websites.

“The wrong way to do it is to engage in crystal ball gazing and rumouring,” he says. “You can find a rumour about anything you could think of in the FDA – it’s public sport.

“Before I got involved in the higher levels of the FDA I always understood that public pressure, consumer advocacy and, more often of late, patient advocacy, were the driving force. That part is true, but the driving vehicle for the force is the Congress.

“The Congress has the power – White Houses that I’ve worked for and worked in generally don’t exert much power in FDA. They take credit for a lot of things and little blame for anything.

“Any change has to be approved by Congress and voted on or else FDA has no authority. They can’t issue a regulation unless there is enabling legislation, a law or most often an amendment. Some of these amendments are only 60 words long but they change everything.

“You can have a bill for the preservation of the aardvark or something like that and they’ll add an amendment on biosimilars or something. Usually they are thrown out because they are not germane, but if you listen to some of the people like Senator (Ted) Kennedy explain germaneness to you, it doesn’t matter if it is germane or not. If it is germane to him it’s germane.”

The US FDA consists of five functional departments, the most well known being food and drugs. Veterinary medicine, which is Crawford’s speciality, is what he calls the “Cindarella child” because no one pays it any attention.

Medical devices is different because it is run by engineers. “Remember that when you go in there you have to have engineering-speak, and they hang out in a new multimillion dollar engineering physics lab at the new White Oaks facility, so that’s a different character. People trying to deal with the medical device centre in the same way as they do with the drug centre they are going to fail, because they are nothing like that.

“And biologics is totally different – they have no resemblance to drugs or medical devices. Why? Because they are situated on the NIH campus and they still do not accept that they are members of the FDA and don’t want to accept it.

“There’s no harmony between them and if you do have an issue that involves two centres working on your drug be sure and insist that there be a lead centre and it might be better if the lead centre is not drugs.

“I think it is important for start-up companies, biotechs in particular, to have someone on the ground in the US. It can be somebody from Australia who is stationed there, but inevitably you will need to hire some consultants, technical consultants, who put the package together for you and give you some advice on the best route.

“I don’t know any company that has succeeded without having someone on the ground in the US. These people don’t have to have had worked at the FDA but they do have to have about three characteristics: one, they have a great interest in it and understand it in all of its ramifications; second, they have to have a respect for it; and then third they have to understand that part of it is diplomacy.

“That also means that if you are going to be diplomatic that precludes the hammer over the top of the head approach, because that is not going to make it.”