WASHINGTON (AP) -- Weeks before President Bush announced a plan to protect African babies from AIDS, top U.S. health officials were warned that research on the key drug was flawed and may have underreported thousands of severe reactions including deaths, government documents show.
The 2002 warnings about the drug, nevirapine, were serious enough to suspend testing for more than a year, let Uganda's government know of the dangers and prompt the drug's maker to pull its request for permission to use the medicine to protect newborns in the United States.
But the National Institutes of Health, the government's premier health research agency, chose not to inform the White House as it scrambled to keep its experts' concerns from scuttling the use of nevirapine in Africa as a cheap solution, according to documents obtained by The Associated Press.
"Everyone recognized the enormity that this decision could have on the worldwide use of nevirapine to interrupt mother-baby transmission," NIH's AIDS research chief, Dr. Edmund C. Tramont, reported March 14, 2002, to his boss, Anthony Fauci, director of the National Institute of Allergy and Infectious Diseases.
The documents show Tramont and other NIH officials dismissed the problems with the nevirapine research in Uganda as overblown and were slow to report safety concerns to the Food and Drug Administration.
NIH's nevirapine research in Uganda was so riddled with sloppy record keeping that NIH investigators couldn't be sure from patient records which mothers got the drug. Instead, they had to use blood samples to confirm doses, the documents show.
Less than a month after Bush announced a $500 million plan to push nevirapine across Africa to slow the AIDS epidemic, the Health and Human Services Department sent a nine-page letter to Ugandan officials identifying violations of federal patient protection rules by NIH's research.
The NIH research "may have represented a failure to minimize risk to the subjects," the Office of Human Research Protections told Ugandan authorities in summer 2002.
Africa accounts for more than two-thirds of the world's AIDS cases, with 27 million infected, and the United States sought to help slow the disease's spread across the continent.
Nevertheless, NIH officials told AP they remain confident after re-reviewing the Uganda study and other research that nevirapine can be used safely in single doses by African mothers and children to prevent HIV transmissions during birth. But they acknowledged their Uganda research failed to meet required U.S. standards.
As a result, NIH recently asked the National Academy of Sciences to investigate its science in the case, and has spent millions in the past two years improving its safety monitoring and record keeping.
"I would say there are many lessons that we have learned from this review that will help us do our clinical research, both domestically and internationally, much better," said Dr. H. Clifford Lane, NIH's No. 2 infectious disease official.
One lesson derived from a closer review of the Uganda research is that even single doses of nevirapine can create instant resistance, meaning patients may not be able to use the drug or others in its class again when their AIDS worsens, Lane said.
"It was unexpected, and what it means is nevirapine probably shouldn't be a drug of first choice if other options are available," Lane said.
Lane said NIH officials were aware in spring 2002 about the impending White House announcement on nevirapine but did not tell presidential aides of the problems because they were confident, even before reviewing the Uganda research, that the underlying science was solid.
The White House -- though unaware of the NIH concerns -- also remains confident in Bush's $500 million plan in 2002 to send nevirapine to Africa. Bush approved $2.9 billion for global AIDS fighting next year.
"The president's mission is to try to stop the spread of AIDS in Africa and to come at it from a new angle, and that is what this is all about," spokesman Trent Duffy said.
Nevirapine is an antiretroviral drug marketed in the United States as Viramune that has been used since the 1990s to treat adult AIDS patients and is known to have potentially lethal effects like liver damage and severe rashes when taken over time.
In 1997, NIH began studying in Uganda whether it could be given safely in single doses to stop mother-to-baby transmissions. That research showed it could reduce transmission in as many as half the births.
But by early 2002, an NIH auditor, the agency's medical safety experts and the drug's maker all disclosed widespread problems about the U.S.-funded research in Uganda.
Boehringer Ingelheim, the Connecticut-based company that makes nevirapine, told NIH it identified at least one "critical compliance issue" that compromised the integrity of the study and more than four dozen issues it described as "serious" and "major."
Boehringer and NIH auditors cited concerns such as failing to get patients' consent about changes in the experiment, administering wrong doses and delays and underreporting of "fatal and life threatening" problems.
"It appeared likely, in fact, that many adverse events and perhaps a significant number of serious adverse events for both mother and infant may not have been collected or reported in a timely manner," Westat Corp. reported in March 2002. Westat is a professional medical auditing firm hired by NIH to visit and audit the Uganda site.
Westat reported there were 14 deaths not reported in the study database as of early 2002 and that the top two researchers in Uganda acknowledged "thousands" of bad reactions that weren't disclosed.
NIH said the subsequent review whittled that list down significantly, all deaths were eventually recorded and the majority of bad reactions are believed to have been caused by the poor health of patients, not the single dose of nevirapine. But they conceded it was incumbent on a U.S. research project to fully and quickly disclose them.
Officials said the problems began when NIH converted the research from determining the drug's usefulness to supporting FDA approval for the drug. Paperwork in Uganda wasn't kept to the FDA standards, they said.
"We may not have reported exhaustively, but we reported all serious side effects," said Professor Francis Mmiro, a lead doctor in the Uganda study. "What you may call a serious side effect in the U.S. is not a serious side effect in Kampala."
NIH officials reviewed the bad news in early March 2002.
Meeting minutes, written in shorthand, raised broad concerns: Half the babies in the study were also enrolled in a vitamin A study that could have affected the outcome, and medical staff running the trials didn't follow procedures for divulging serious adverse events (SAEs).
"No mtg minutes, no training doc(umentation), site used their own criteria for grading SAEs. No lab normal values & serious underreporting of SAEs," the minutes stated.
The minutes quote an NIH official who visited Uganda as saying, "The site staff doesn't know what they don't know."
But Tramont, the AIDS research chief, and other top NIH officials repeatedly dismissed the concerns as preliminary or overblown, and sought to salvage the flawed research's underlying conclusions rather than start over.
"There is presently no evidence that the study's scientific results are invalid," said a report Tramont sent to his staff less than two weeks after getting the March 2002 Westat audit.
In January 2002, Boehringer sent NIH an early copy of its report. But the drug maker, fearing publicity about the report might destroy its chance to get the FDA approval of the drug for domestic use, asked NIH to destroy it before FDA regulators could learn about it.
"Sensitive information. Asked for it to be destroyed when audit is upon us," NIH official Mary Anne Luzar wrote on the cover page of Boehringer's report.
Boehringer says it never requested the document be destroyed, saying "our actions throughout the study evaluation were proactive and forthcoming."
Lane said the request to destroy the report was inappropriate and NIH never complied. But he conceded his agency inappropriately kept the audit from FDA for weeks, saying, "It shouldn't have happened that way."
NIH at first sought to postpone the FDA review of nevirapine, then top NIH and FDA officials arranged for the drug maker to pull its U.S. application rather than risk a public rejection that might scare African countries looking for U.S. guidance on the drug.
Unaware of the internal NIH concerns, Bush announced in June 2002 a $500 million effort to fight the spread of AIDS in Africa and the Caribbean. The plan's centerpiece was nevirapine.
"This major commitment of my government to prevent mother-to-child HIV transmission is the first of this scale by any government, anywhere," Bush said in a Rose Garden announcement. The White House hoped the initiative would reach up to 1 million women a year and cut mother-to-child transmission of HIV by up to 40 percent.
Two years later, after hundreds of thousands of doses of nevirapine have been distributed to African mothers and children, the FDA has recommended NIH stop using the drug with certain patients. It also has demanded stronger warnings to doctors and patients about possible lethal liver damage and rashes in patients who take nevirapine for longer periods of time.
African health officials are having second thoughts. South African officials in July recommended ending the single-use treatment because of the new concerns about drug resistance.
African doctors said they weren't aware of the full extent of NIH's concerns but feel comfortable -- at least until better options emerge -- administering it in single doses to AIDS-sickened mothers who have few other choices to protect newborns.
"It's not ideal, but it works," said Dr. Ashraf Coovadia of Coronation Mother and Child Hospital in Johannesburg, South Africa. Without it, "many, many more babies would be born with HIV."
Boehringer Ingelheim said it has donated enough doses to treat more than 411,000 mothers and infants in Africa, and self disclosed the problems it found with the Uganda research. But it says it has research from other locations, like Thailand and South Africa, showing single dose usage at birth is safe and effective.
"The bottom line is there were these procedural issues, such as the speed of reporting adverse events, and the like. But the important scientific data was intact, and found to be valid," said Dr. Patrick Robinson, a top Boehringer AIDS specialist.
Still, the German-owned company no longer is seeking FDA permission to use nevirapine for protecting U.S. infants because better treatments have emerged, he said.
General news >> Saturday February 03, 2007 EDITORIAL
Your medication: Is it genuine?
Any mention of copyright violations usually brings to mind pirated DVDs, software, music and the challenges posed to legitimate, paying users by error-prone and frustrating digital rights management programs designed to combat such infringements. It can all sound relatively harmless and create the misconception among some people that piracy is essentially a victimless crime. This is definitely not the case. The singer or musician whose work is stolen is a victim, and the Thai software engineer whose work is copied without recompense loses his livelihood. What is rightfully theirs goes into the pockets of criminal gangs.
But the most sinister aspect of this trade in fake goods, and one those people who try to rationalise taking advantage of and making such purchases usually overlook, is that counterfeiting is all-pervasive, with few areas left untouched. Consumers are in danger of discovering just how widespread and hazardous it can be when the medicine they buy from the pharmacy or clinic, or the new brake linings they purchase for their car, also turn out to be masquerading under a fake brand name. The likelihood is that these counterfeits will be substandard and possess the potential to seriously harm or kill them. A frighteningly true example of caveat emptor or let the buyer beware.
The counterfeiting of ordinary medicines has become big business for unscrupulous criminal gangs and, tragically, it continues to be a growth industry with truly horrific results. One pharmacist in the United States was even convicted of adulterating and counterfeiting cancer treatment drugs so he could enrich himself by increasing the suffering of cancer victims. He was caught, but arrest rates in our part of the world are ominously low.
There is no shortage of international concern. The World Health Organisation (WHO), World Bank and Interpol have long expressed concern at the proliferation of counterfeit medicines and they were joined this week by the World Intellectual Property Organisation, which took up the matter at its annual meeting in Geneva. Industry specialists put the cost of such counterfeiting at more than $100 billion a year and warned just how much it was putting human health and safety at risk while, at the same time, undermining economic development through lost earnings, lost jobs and lost tax revenues.
Delegates did not raise any eyebrows when members of the organisation declared China to be the worst offender in the trade of fake goods, with every product on the market being a target for counterfeiters. They already knew that two-thirds of all bogus goods seized by European Union customs officials came from China. But they could not fail to be shocked at hearing that 10% of the world's medicines are fakes. And this was a conservative estimate. The WHO believes that up to 25% of prescription drugs sold in developing countries are pirated and consequently a menace to public health.
The most commonly counterfeited medicines are treatments for life-threatening conditions such as HIV/Aids, tuberculosis and, especially, drug-resistant malaria. The malaria problem, endemic in border areas, is worsened by the roaring trade in fakes, including the new and effective Artemisinin-based Combination Therapy (ACT) drugs. The counterfeiters follow where people are buying these drugs, counterfeit them and put them on the market and all of a sudden, the medicine stops working. For the drugs to be safe and effective, they have to be what they say they are. Patients die when they are not.
The Public Health Ministry publishes photos of seized counterfeits on its website. Its researchers say they regard China as the main instigator because only 5% of the contents of some of its drugs are medical substances while over 90% can be just glucose.
Concerted efforts are being made to stem the flow, but this problem needs to be tackled at the source, which puts the onus on Beijing _ a regime which has shown just how tough it can get when it really wants to. Ending this despicable trade in human suffering and greed should provide sufficient impetus to act.
February 9, 2007
BANGKOK AFP) - Thailand said Friday it has opened talks with US drugmaker Abbott Laboratories on lowering the price of an AIDS treatment, which could avoid the need for a generic version Bangkok approved last week.
Thailand has already issued a so-called "compulsory license" for the anti-AIDS drug Kaletra, which effectively breaks the drug's patent and clears the way for the kingdom to either produce or import cheaper generic versions.
Hoping to prevent Thailand from turning to generics, Abbott has agreed to work with the kingdom to find ways of reducing the cost of treatment, the health ministry said.
"Abbott has agreed in principle with the Thai government to make Kaletra more affordable for all Thais," said Suvit Wibulpolprasert, the ministry's senior advisor on health economics.
"They have not yet agreed to cut the price, but we are in negotiations over that," Suvit told AFP.
AIDS activists say that generic versions of Kaletra would cut the cost of treatment to 4,000 baht (114 dollars) per month from the current 11,580 baht (331 dollars).
Thailand's universal HIV/AIDS treatment programme has been hailed as a success in the fight against the disease.
In 2002, the Thai government launched a generic version of an HIV/AIDS triple therapy and was able to cut the cost of treatment 18-fold.
Thailand's treatment program has been widely credited with slashing the number of AIDS deaths by about 75 percent last year and the number of new annual HIV infections continues to drop.
In November, Thailand decided to allow generic versions of pharmaceutical giant Merck's high-priced HIV/AIDS drug Efavirenz.
Merck already agreed to cut the price of Efavirenz from 1,300 baht to 880 baht, as Thailand is starting to import the drug from India at the price of 650 baht, Suvit said.
นับเป็นการ "ลองของ" ของประเทศที่พึ่งพัฒนาแล้วอย่างไทย ด้วยการบังคับใช้สิทธิในการผลิตยาเองโดยการอ้าง Doha Declartion on TRIPs and Public Health ต่อกรกับบริษัทยาข้ามชาติ โดยเฉพาะอย่างยิ่ง บริษัทยาที่ทรงอิทธิพลอย่าง สหรัฐ-สหภาพยุโรป ที่เป็นเจ้าของสิทธิบัตรสำคัญในตัวยาที่จำเป็นต่อการรักษาในประเทศโลกที่สาม