Celgene Voice Recognition Helps Manage Medical Risks
Just a few tablets of thalidomide taken in early pregnancy causes babies to be born with webbed limbs or no limbs at all. Back in the 1950s, women took thalidomide, which was developed by a German company called Chemie Grunenthal, for morning sickness. It was not until 1961 that a German pediatrician made the connection between the seemingly innocuous drug and the deformed babies. The drug was taken off the market, but not before 10,000 severe birth defects in 46 countries were traced by health authorities back to the drug's use.
Since then, thalidomide has been found effective in combating other illnesses, including cancer and erythema nodosum leprosum (ENL), an inflammation that accompanies leprosy. In 1998, the Food and Drug Administration approved thalidomide for treatment of ENL. And while the drug hasn't been approved for cancer treatment, more than 90% of thalidomide prescriptions now go to cancer patients. Since 1998, about 130,000 people have taken the drug.
Thanks in part to a voice recognition system developed by Celgene, the Summit, N.J.-based biopharmaceutical company that licensed and commercialized thalidomide, there have been no reported birth defects caused by the drug, which Celgene sells as Thalomid. The system, called S.T.E.P.S.System for Thalidomide Education and Prescribing Safetywas developed by Celgene in-house for $20 million and approved by the FDA.
S.T.E.P.S. is a network of Oracle database, fax, image storage, telecommunications and Interactive Voice Response (IVR) servers that keeps records on all who handle Thalomidincluding doctors and pharmacists as well as patients. Before any prescription can be filled, all three parties must fax in a registration form. The doctor assists the patient in completing the form, which identifies the patient's risk category (e.g., female, childbearing age).
At several points during the process of getting or refilling a prescription, patients, pharmacists and doctors must call the IVR system and answer a series of questions about how they are using or dispensing the drug. If there are problems or wrong answers, the IVR transfers the call to a Celgene representative. S.T.E.P.S. also tracks the whereabouts of Thalomid packages by attaching authorization numbers to each prescription.
But not everyone is thrilled with the results.
Health-care workers who use S.T.E.P.S. say it's the most restrictive system they've encountered in their medical careersso restrictive that it is sometimes inconvenient to use. For example, Katy Welch, a registered nurse at the University of Arkansas' Myeloma Institute, finds it frustrating that patients must be reprocessed through S.T.E.P.S. if they can't fill their prescriptions within Celgene's deadline, which is seven days.
And some critics, including Richard Blumenthal, attorney general of Connecticut, say the system should be adapted to track new potential risks, such as blood clots, that have recently been associated with the drug when used as a cancer treatment.
Thalomid can be an effective cancer drug for the same reason that it harms developing fetuses: It inhibits the growth of new blood vessels that feed tumors. But a potentially lethal side effect is blood clots, especially when patients are taking Thalomid along with other chemotherapy.
Twelve patients out of 190 died of blood clots while taking Thalomid for renal cell cancer, according to the Research on Adverse Drug Events and Reports project, which published a paper on drug side effects in May in The Journal of the American Medical Association. The group, funded by the National Cancer Institute and other organizations, figured that between 1 in 3 and 1 in 5 patients were developing blood clots in these clinical trials.
"Cancer drugs are the most toxic, and cancer patients have the worst prognosis," says Dr. Charles Bennett, a professor of medicine at Northwestern University in Evanston, Ill., who works with the project. "It's not surprising that off-label use in cancer may be more adventurous."
In May, Blumenthal petitioned the FDA to require Celgene to change S.T.E.P.S. so it would also track blood clots. Blumenthal wants Celgene, relying on clinical data from the research project, to create a seventh category of patient in addition to the six who are divided by age, sex and fertilitypatients who use Thalomid concurrently with other chemotherapy. He also wants Celgene to add questions to S.T.E.P.S.' voice response system so the program is collecting information on risk factors for blood clots. And he wants all blood clots reported to Celgene and the FDA.
So far, Celgene says it has no plans to change S.T.E.P.S.
Celgene's executive director of information technology, Steve Lerner, says the company already has a system to track all of its drugs' side effects, including blood clots, and that the sole purpose of S.T.E.P.S. is to prevent birth defects caused by thalidomide. He says no one at Celgene has asked him to change the system to track blood clots, although "if the FDA asks [Celgene] to do something, we'll do it."
In a letter to Blumenthal on Oct. 31, the FDA said it is still studying the petition and has not reached a decision.
Meanwhile, S.T.E.P.S. will be part of a new system that the FDA hopes will stop birth defects caused by another drugAccutane, known generically as isotretinoin, a medication produced by several manufacturers that is used to treat severe acne. The FDA believes isotretinoin has caused at least 160 birth defects since 1982, in addition to untold miscarriages. After several voluntary registries run by the drug manufacturers failed to stop pregnancies, Celgene in 2004 licensed its patents for S.T.E.P.S. to four manufacturers, which are building a system due in 2006 to control the distribution of Accutane.
But the March of Dimes says it will be far harder to control access to Accutane than to thalidomide. Millions of women of childbearing age use the anti-acne drug, according to Dr. Nancy S. Green, the March of Dimes' medical director, compared to the 130,000 patients who have taken Thalomid. Also, Accutane goes by many other names, making the task of tracking the drug more complex.
"There's no guarantee that this system will work on such a widely distributed drug," Green says.Can't Track Everything'">
'Can't Track Everything'
What has happened with thalidomide since the FDA approved it shows how hard it can be for companies and government organizations to manage risk, even when they have made what appear to be the best-laid plans.
One consultant suggests that even though risks are never static, few companies have processes in place that can prepare them for every problem.
"The business owner says, 'I can't track everything,'" says Jeff Weber, the managing director of Protiviti, a subsidiary of Robert Half International that advises companies on how to identify and keep reassessing business and technology risks. "But do you [just] assess the risk that hits you in the head?"
S.T.E.P.S. is a fairly straightforward system. It is part of a class of systems called performance-linked access that are mandated by the FDA to control dangerous drugs.
Celgene provides doctors with software to generate forms and an education kit that includes pictures of babies deformed by thalidomide. Before prescribing any drug, the doctor must show the patient the pictures to emphasize the dangers of taking thalidomide, and female patients of childbearing age must have had a pregnancy test and been using two forms of contraception for a month.
The patient signs the consent form, and doctor and patient each call the IVR to answer questions on such things as how much of the drug has been prescribed and whether pregnancy tests, if applicable, are negative. If their answers are inconsistent, someone from Celgene intervenes.
If the answers are consistent, Celgene's system generates an authorization number for the doctor to write on the patient's prescription. The patient then carries the prescription to the pharmacist, who calls the system to see if the authorization number is valid. If so, Celgene's system checks that the amount being confirmed is in line with authorized prescriptions to prevent unauthorized orders of the drug. Pills are shipped in blister packsmolded plastic sealed to backing that can't be cut, so the patient can't share medication. Before each renewal, the patient must again visit the doctor, have another pregnancy test and call the IVR to answer questions on safe behavior, such as whether she has used two forms of contraception while taking Thalomid.
S.T.E.P.S. works for what it does. A more useful system, however, would track all side effects of the drug in real time, over the Web, so doctors could immediately assess whether patients should receive it, according to Dr. Richard Gliklich, CEO of Outcome Sciences, a Cambridge, Mass.-based consultant for companies that have had drugs or devices approved by the FDA. Such a system could be linked with online prescribing, which could happen in the background.
But those systems don't exist today. One reason is that technical standards like HL7, which determines how these systems would swap data, are still being defined. "Right now, if the FDA mandates a performance-linked access system [like S.T.E.P.S.] to a drug, it's not the best news for the pharma company," Gliklich says. He expects a big improvement in such systems by 2010.
As of late November, Celgene was trying to convince the FDA to approve what the company says is the first of several successors to Thalomida chemical analog called Revlimid that Celgene says won't cause birth defects.
Mercedes Benegbi, executive director of the Thalidomide Victims Association of Canada, says Celgene promised the victims' group in 1997 that it would develop a drug like Revlimid and take Thalomid off the market. In return, the group agreed not to oppose Celgene when the company asked the FDA to approve thalidomide, she says.
"We asked Celgene to be honest, and we trust that all the information they provide to us is true," says Benegbi, who was born with defects caused by thalidomide.Cash Cow in a Pill">
Cash Cow in a Pill
Right now, however, Celgene can't afford to stop selling Thalomid. For 2005, the company projects that around 76% of its revenue will come from Thalomid sales, down from 82% in 2004. One reason the 2005 percentage isn't lower is that in October the FDA delayed approval of Revlimid.
The FDA wants more time to review Celgene's risk management program. Lerner speculates the agency fears that Revlimid, like Thalomid, could cause birth defects, despite the absence of evidence for that notion in tests with animals. So Celgene is building a S.T.E.P.S.-like risk management system called RevAssist to control access to the drug. Lerner declines to discuss how RevAssist will work because its features are under discussion with the FDA.
Regardless of whether the FDA forces Celgene to change S.T.E.P.S., doctors who prescribe Thalomid expect it to become more widely used in January, when the drug, which can cost $1,500 a month, is covered by Medicare and more patients can afford it.
Northwestern's Bennett believes wider availability of Thalomid will mean more danger of side effects, although Celgene spokesman Brian Gill says the side effects are tolerable, well documented and clinically manageable.
But Bennett says the FDA has few resources to track drugs it has already approved, particularly when they are prescribed off-label for diseases like cancer that may kill people anyway.
One suggestion, from Gliklich, is that the FDA create "safety registries"databases that the agency could use to study a sample of people who are taking an already approved drug.
"You don't need every patient for blood clots in a S.T.E.P.S. program," Gliklich says. But he believes the registries would allow the FDA to study the new problems that inevitably crop up after a drug is approved and doctors start prescribing it off-label for unapproved treatments.Celgene Base Case">
Celgene Base CaseHeadquarters: 86 Morris Ave., Summit, NJ 07901
Phone: (908) 673-9000
Business: Discovering, developing and commercializing pharmaceuticals
Information Technology Director: Steve Lerner
Financials in 2004: $377.5 million in revenue; $52.8 million in net income.
Challenge: To put in place an information system that will help prevent drug side effects such as birth defects, miscarriages and blood clots.
- Boost revenue by 39% to $525 million in 2005, from $377.5 million in 2004.
- Generate $400 million in sales of Thalomid in 2005, an increase of 29.6% from $308.6 million in 2004.
- Raise R&D spending by 24.3% to $200 million in 2005, from $160.9 million the previous year.
- Increase selling, general and administrative expenses to $175 million in 2005, from $114.2 million in 2004, to support the launch of Revlimid.