COVER STORY

HOW SAFE IS THE DRUG SUPPLY?

Reports of counterfeit drugs and the growth of e-tailing are fanning concerns about drug quality

It started last December, when Serono started getting calls from a handful of California AIDS patients who said their latest prescriptions of Serostim (somatropin) 6 mg had caused a skin irritation or just didn't look the same.

The Massachusetts-based company soon discovered a simple—and frightening—explanation. While the packaging looked similar and bore an authentic lot number, the product inside was counterfeit. Perhaps more troubling, pharmacies in six other states also found phony Serostim on their shelves.

Serono and its Serostim users were victimized again in May with another batch of fakes. In the interim, Amgen spotted that the contents of eight vials of Epogen (epoetin alfa) and Neupogen (filgrastim) had been removed and replaced with a nontoxic, but nonsterile solution. Amgen found different counterfeit lots of Neupo-gen in May and June. Also in May, Genentech said pharmacies in California, Florida, and Indiana had uncovered bogus Nutropin (somatropin).

Who made the counterfeits, where, and precisely how they got into pharmacies remain part of an active criminal investigation, according to the Food & Drug Administration and officials of the companies. While the culprits are unidentified, their motives to many seem clear—money. A three-month regimen of Serostim, for example, usually costs about $20,000.

Money, too, seems to be at the root of a case perhaps even more vexing to pharmacists. In August, Missouri R.Ph. Robert R. Courtney was charged in federal court with allegedly diluting at least 150 bags of IV chemotherapy drugs to boost his profits. He is awaiting trial on tampering, adulteration, and misbranding charges. More charges may be filed, including manslaughter or homicide, if investigators link the diluted drugs to patient deaths. The incident prompted Sen. Christopher S. Bond (R, Mo.) to question whether pharmacists are regulated enough. In a letter to Health & Human Services secretary Tommy Thompson, Bond asked whether the federal government should play a larger part in "policing the conduct of pharmacists."

What's going on? How safe is the U.S. drug supply? How can pharmacists protect their patients and themselves? And what about terrorism? Are pharmacists' drug supply vulnerable?

There's no question that more drugs of unknown safety, efficacy, and origin are in circulation now than just a few years ago. Millions of people are buying what are advertised as bargain-rate prescription drugs from offshore Web sites with no questions—except for credit card numbers—asked. Countless others are visiting Mexico, where prescriptions are not required for most medicines and are easily obtained for controlled substances, including OxyContin (oxycodone HCl, Purdue Pharma).

"There is no magic force field that protects the United States from imported counterfeit or diverted products," said Rep. James C. Greenwood, chairman of the House Energy & Commerce Committee's subcommittee on oversight and investigations. "We must be aware of the latest threats in the global pharmaceutical market and deal with them." Like most others before the terrorist attacks on the Twin Towers and the Pentagon, Greenwood believed the U.S. drug supply was "extremely safe" overall. But he cautioned: "The risk is not zero."

Of course not, but Congress thought it had dealt with much of the problem in 1988 when it passed the Prescription Drug Marketing Act (PDMA). To a large degree, it was spurred by the discovery of two million birth control pills meant to look like G.D. Searle's Ovulen-21. However, they contained little or no estrogen. They seem to have originated in Spain, were shipped to Guatemala, smuggled across the U.S. border, and wound up in American pharmacies. A Panamanian bank account held $200,000 in profits. In another case in 1985, the FDA seized 1,800 bottles of counterfeit Ceclor (cefaclor, Lilly) during a Customs inspection.

PDMA was meant to sweep away the murky gray market in diverted prescription drugs. That market is fed by American goods shipped to charities overseas (although sometimes they never left the docks) and the resale of free Rx samples and medicines originally sold at sharply reduced rates to hospitals, nursing homes, and clinics. But the law didn't get rid of the gray market entirely, and now the profit margins are even higher.

"It's a $2 billion blight on the economy of the country, and people are being held hostage for flu vaccines and other things," Keith Macdonald , executive secretary of the Nevada State Board of Pharmacy, told Drug Topics. Right now, he is looking into a wholesaler offering a flu vaccine that is in short supply for nearly double the average wholesale price and about six times the Federal Supply Schedule charge.

Macdonald has drafted a resolution for his board to consider that would deny a wholesaler's license to those that don't sell at least 90% of their products to pharmacies, hospitals, clinics, or doctors. Where do they get their products? "They claim 'opportunity buying'—buying short-dated products or products on which the price is going to go up in six months, so they buy a big pile of it so they can win on the price," Macdonald said. "But that's all palaver. About 90% of their product is obtained by diversion—purchases from closed-door pharmacies and other places."

The National Association of Boards of Pharmacy (NABP) asked for a federal investigation into closed-door pharmacies (so called because they don't serve walk-in customers, just nursing homes) and other institutions that sell their medicines at as much as 99% less than what retail pharmacies are charged. An NABP task force said closed-door pharmacies are "reselling discounted pharmaceuticals at a significant profit to secondary source wholesalers who resell them at a significant profit to other secondary source wholesalers, or even to primary wholesalers, who can purchase them for less than they can purchase the products from the manufacturers."

An apparent loophole in FDA regulations implementing PDMA may have opened the way for closed-door pharmacies. It seems to allow entities that service nursing homes and long-term care patients to resell discounted drugs.

The FDA's plan to address part of the situation has run into opposition on Capitol Hill. The agency originally wanted secondary wholesalers who don't have direct relationships with drug manufacturers to give customers an extensive "pedigree," identifying all the hands the drug passed through to reach them. But, manufacturers and so-called authorized wholesalers are not required to pass on pedigrees.

A bill is pending in Congress that would require secondary wholesalers (there are an estimated 6,500 of them, and 83% of them have fewer than 20 employees) to certify the source of their product and drop the pedigree provision. It also would expand the definition of authorized wholesaler.

Although samples and returned American goods seem to be less of a problem under PDMA, a law written 13 years ago could not have foreseen the rise of the Internet and its use to market prescription drugs. While rogue domestic Web sites remain a concern, state and federal authorities have put some of them out of business. And, NABP has given concerned consumers a big help with a certification program. But offshore facilities, beyond the reach of U.S. law, remain a threat.

About two million parcels containing foreign drug products intended for personal use flood the 13 international mail facilities each year, according to FDA estimates. Customs Service officials report that they also see wholesale quantities. Although X-rays by Customs usually spot the drugs, the sheer volume presents a daunting task. FDA inspectors, if they are present, can perform a field test to determine whether the product contains the correct active ingredient.

But they can't immediately tell if it's the right amount, expired, or contaminated. That can cost up to $15,000 in a lab. And, counterfeiters are nothing if not clever. Expertly copied drugs, in size, color, and packaging, often can fool all but a few inside the company. Sometimes the con men intermingle shipments of genuine, adulterated, expired, and counterfeit product to make testing seem like Russian roulette.

After laboratory analysis, the FDA was able to determine that the first lot of fake Serostim contained a naturally occurring hormone called HCG, or human chorionic gonadotropin, said company spokeswoman Carolyn Castel. The second batch contained small amounts of human growth hormone, but not enough to be effective, and it definitely was not Serostim, she added. At least one vial of the bogus Nutropin contained human insulin.

If FDA inspectors determine that a parcel should not be allowed in, they must issue a notice of potential violation to the addressee and give the individual a chance to respond. Although virtually all foreign shipments are illegal, the FDA has hamstrung itself with a "personal importation" rule it originally designed for humanitarian purposes to let critically ill patients obtain unapproved products. Closing the opened flood gates would bring a certain court challenge the agency conceivably could lose, so at least 90% of the packages are sent on their way unimpeded.

What do they contain? Rep. John Dingell (D, Mich.), father of PDMA, asked an FDA official at a hearing recently if many of the products "may be counterfeit, expired, super-potent, sub-potent, simply tainted, or mislabeled so as to constitute something other than what it appears to be, possibly even including Schedule I substances." Replied FDA senior associate commissioner William Hubbard: "It is highly likely that is correct."

Hubbard said the FDA would recommend to its bosses at the HHS that the Customs Service turn back virtually all personal-use Rx parcels from overseas. But whether the Bush Administration will endorse that suggestion or some in Congress will try to move on their own is unclear at this juncture. Since the terrorist attacks of Sept. 11, both Congress and the Administration have become "other focused" in the words of Sherry J. Haber, v.p. for government relations at the Healthcare Distribution Management Association. "Their first priority is national defense," she said.

The change in focus also affects the broader question of reimporting U.S.-made drugs or importing those made in FDA-inspected foreign plants or from certain countries. The Bush Administration, as did the Clinton Administration before it, has come out against reimportation in general as well as by pharmacists and wholesalers.

HHS secretary Thompson said this summer "opening our borders ... would increase the likelihood that the shelves of our pharmacies in towns and communities across the nation would include counterfeit drugs, cheap foreign copies of FDA-drugs, expired drugs, contaminated drugs, and drugs stored under inappropriate and unsafe conditions." Reimportation's only pharmacy booster, the National Community Pharmacists Association (NCPA), has challenged that view repeatedly.

When Thomson announced his decision, NCPA president John Carson expressed disappointment and said, "Millions of Americans are crossing our nation's border—both physically and via the Internet—to purchase prescription drugs at lower prices with little or no assurance of safety." NCPA supports importation of drugs made in FDA-approved facilities by indepen-dents and buying groups. Stephen Giroux, who owns a pharmacy in Middleport, N.Y., close to the Canadian border, said at a hearing last month that he would be "totally confident and comfortable buying these [Rx] products from a Canadian supplier."

A Congressional staffer, who asked not to be named, said foreign Internet prescription sales and reimportation could suffer collateral damage from the Sept. 11 attacks. "I think that recent events have got to have changed the calculus," he said. "[They are] a subset of greater concerns about control of our borders."

Rep. Greenwood, who supports both the foreign mail ban and no reimportation, said in an interview with Drug Topics that he is now concerned not only with greedy counterfeiters but also with political terrorists seeking to damage the U.S. drug supply. He doesn't believe it's vulnerable to terrorists "in a big way. It's too diversified and too decentralized. But, just like you can hit one building, you can hit one feed stock. So, we have to be cautious ... without being alarmist."

Michael F. Conlan

WHAT TO DO

Here's some advice on how to avoid counterfeit drugs for pharmacists and consumers from the American Pharmaceutical Association:

• Be observant about the appearance of the packaging and medicine you receive and alert to any changes from one prescription lot number to the next. Talk to your pharmacist if you have any questions about your medication.

• Always buy medications from a highly reputable source.

• Be wary of "special deals" or marked reductions in product price that may represent promotion of a counterfeit.

• Be careful when buying medications on-line. Avoid buying medications from on-line pharmacies not licensed in the United States, or from on-line stores that offer either to sell medications without prescriptions or to write prescriptions. Reputable on-line pharmacies will have a seal of approval called VIPPS, or a Verified Internet Pharmacy Practice Site, provided by the National Association of Boards of Pharmacy.

• Pharmacists and doctors should report suspected counterfeiting to the FDA MedWatch program at www.fda.gov/medwatch/index.html or 1-(800) FDA-1088 and to the pharmaceutical manufacturer.

 

Mike Conlan. HOW SAFE IS THE DRUG SUPPLY?. Drug Topics 2001;21:32.