As early as 2000, U.S. health authorities raised concerns about the French breast implant maker at the heart of a scandal affecting hundreds of thousands of women worldwide. That was almost 10 years before the company came under scrutiny from European regulators.The U.S. Food and Drug Administration sent an investigator to inspect a plant run by the manufacturer, Poly Implant Prothese (PIP), at La Seyne Sur Mer in southeastern France in May 2000. Shortly afterward, the FDA sent the company's founder, Jean-Claude Mas, a warning letter saying the implants were "adulterated" and citing at least 11 deviations from good manufacturing practices.
The problems had to do with PIP's saline implants, a different line from the silicone implants that French authorities ordered off the market in 2010 for using industrial-grade silicone instead of medical-grade silicone, leading to the French company's bankruptcy. Still, the plant inspected by the FDA was used to manufacture the silicone implants for PIP.
The French government last week recommended that women in France who have PIP's silicone gel-filled implants get them removed by their surgeons after the implants appeared to have an unusually high rupture rate. Other countries, including Britain and Brazil, said women should visit their surgeons for checks.
A critical question is why the FDA's warning did not trigger greater scrutiny of PIP's activities by regulators in France and elsewhere.
France's drug and medical device regulator, AFSSAPS, told Reuters on Tuesday that it had not found evidence that the FDA had informed them of the 2000 letter sent to PIP.
"The FDA wouldn't be obliged to send it to us if there wasn't a health risk," said a spokeswoman. "Therefore there doesn't seem to be a reason why we would have been informed."
The FDA warning letter was made public in 2000. The agency said it also routinely exchanges non-public information with foreign regulators with whom it has confidentiality commitments, including France. But the FDA could not immediately comment on whether it had shared information with France in 2000.
POOR HEALTH
No one has been charged in the PIP case.
Sources said a Marseilles court could soon announce fraud charges against four to six ex-PIP employees.
There is also an investigation into involuntary homicide by French authorities, following the death from cancer of a woman last year. She had received PIP implants. The French government has not presented any evidence of an increased cancer risk from the product.
Mas' lawyer Yves Haddad told Reuters on Monday that his 72-year-old client was in poor health but ready to respond to any court summons. Haddad denied that Mas was in hiding, reiterating that he was still in southern France's Var region.
"He's currently in very bad health because he has just undergone a difficult surgery that prevents him from walking," Haddad said. "He is worried by the importance this matter is taking on. He is angry at those who pointlessly add to people's suffering," the lawyer added.
Haddad said on Tuesday he did not have details about the FDA inspection as he had only worked for PIP for four or five years.
The U.S. concerns about PIP's saline implants more than 11 years ago could mean that there are safety issues for more women than the 300,000 worldwide who received the company's silicone implants. The number of women with PIP saline implants worldwide and the safety record of the device could not be immediately verified.
The FDA's letter was cited in a lawsuit filed in the U.S. District Court for the Southern District of Texas on behalf of U.S. patients who received the saline implants in the late 1990s, and one who received them as recently as 2001. The plaintiffs said that the implants deflated several years later.
Deflation can be a problem with breast implants. The key issue is whether the incidence suffered by a particular product is higher than health authorities deem to be acceptable.
The FDA's letter is available on the agency's website. Reuters could not ascertain the outcome of the lawsuit, and the lead lawyer, Charles Houssiere, could not be reached for a comment.
The FDA's warning letter, dated June 22, 2000, cited PIP's failure to investigate the deflation of its saline implants and a failure to report more than 120 complaints in France and elsewhere to the FDA. The letter said the plant also did not have a process in place to make sure the implants it produced met design specifications.
NO FORMAL APPROVAL
PIP began selling its saline implants in the United States in September 1996, under a 510(k) accelerated review application that did not require the company to submit clinical trials to show an implant's safety and effectiveness, as long as it was "substantially equivalent" to devices already on the market.
The French company could not sell its silicone-gel implants in the United States at the time because the FDA had prohibited the sale of all such implants from 1992 until 2006 for most women because of safety concerns.
However, for many years, the FDA allowed manufacturers to sell saline implants without formal safety trials, because many were sold before the agency received the authority to regulate medical devices. The agency assumed they were safe unless proven otherwise.
In 2000, due to concerns about possible complications such as infections and rupturing, the agency finally required all implant companies to submit a formal application, known as pre-market approval, to continue selling their products.
PIP was one of three companies that submitted an application, which came under review of a panel of outside advisors to the FDA in March 2000.
At the time, PIP said it had already sold 35,000 of its pre-filled saline implants in the United States, and that it was the third-largest manufacturer of breast implants in the world. It said it only had reports of 521 complaints with its devices, a rate of 1.5 percent.
But the panel recommended that the FDA reject PIP's application. It recommended the implants from the other two companies, Inamed Inc, now part of Allergan Inc and Mentor, now a unit of Johnson & Johnson.
Panelists said at the time they were not reassured by PIP's data, and that the company's clinical trials did not include enough patients that were followed for an adequate time to truly evaluate the device's risks.
"ILL PREPARED"
One panel member, Boyd Burkhardt, a plastic surgeon from Arizona, said the company's data was incomplete, and he found it difficult to understand why the company was "as ill prepared as you appear to be" to meet regulatory standards.
"Like it or not, we have a regulatory threshold which is probably higher or at least different than it is elsewhere in the world, and I think in order to get your product approved, you're just going to have to bite your tongue and meet that threshold," Burkhardt told the company, according to a transcript from the panel's meeting available on the FDA's website.
Asked to comment on the PIP controversy, Burkhardt, in a brief interview, said that he stands by the prior comments he made to the FDA.
It was not immediately clear why after the panel's rejection the FDA then carried out an inspection of the PIP plant in May 2000.
PIP said it stopped selling its saline implants in the United States that same month, according to an SEC filing.