The U.S. Food and Drug Administration has long been the target of both industry and ideological forces seeking to scale back regulation. With a Republican now in the White House, conservatives are once again sounding the call. On February 2, The Wall Street Journal published an editorial railing against the FDA's "costly and archaic system of drug regulation." Enabling consumers to access the "wonder drugs" of the twenty-first century, the Journal argued, requires eliminating "the last century's regulations."
President Bush, who received contributions of $456,000 from the pharmaceutical industry during his 2000 election campaign, will likely prove receptive to such pleas. Conservatives have been pushing Bush to appoint a new, more industry-friendly FDA commissioner. And next year, when key FDA legislation comes up for reauthorization, it is widely expected that pharmaceutical and biotech firms will mobilize their supporters to ease agency regulations.
But this is the wrong remedy for what ails the FDA. In the late 1980s, the FDA embarked on a series of reforms intended to bring new drugs for AIDS and other life-threatening diseases to market more quickly. While many of these early changes were necessary, subsequent laws, passed in 1992 and again in 1997, have taken deregulation too far and left the FDA beholden to the very industry it is supposed to regulate and the public vulnerable to unsafe drugs. Indeed, a large number of medications approved since these reforms went into effect have been withdrawn or severely restricted following reports of severe side effects and deaths. In nearly all these cases, the FDA had clear evidence of the impending health risks at the time of review but nonetheless went ahead with drug approval.
The drive to expedite drug approvals has undermined a review system that was once the world's gold standard. Today "the pressure to meet deadlines is enormous," Dr. Solomon Sobel, director of the FDA's metabolic-and-endocrine-drug division throughout the 1990s, told the Los Angeles Times. "The basic message is to approve." Dr. Rudolph M. Widmark, who served as a medical officer at the agency for 11 years until 1997, declared: "The people in charge don't say, 'Should we approve this drug?' They say, 'Hey, how can we get this drug approved?'" Whereas in the early 1990s the FDA approved 60 percent of the industry's applications for new products, by the end of the decade 80 percent were getting approved.
The federal government normally prohibits the FDA from relying on experts who have financial conflicts, but the agency has waived this restriction more than 800 times since 1998. According to an investigation conducted last year by USA Today, more than half the outside experts hired by the FDA to advise it on the safety and effectiveness of new medical products have financial relationships with pharmaceutical companies that will be affected by their decisions.
The Food and Drug Administration performs no independent drug testing of its own. It relies on the research of the pharmaceutical industry for virtually all of its clinical data on the safety and efficacy of the drugs it regulates. Until recently, the potential for conflicts of interest was moderated by the role of relatively disinterested academic researchers. Over the last decade, however, sweeping changes have enabled the pharmaceutical industry to gain far greater influence over the process of drug testing, development, and FDA approval, thereby threatening the integrity of clinical research itself. As recently as 1991, nearly 80 percent of industry-sponsored clinical trials were performed by experienced investigators in nonprofit academic medical centers. Today, according to CenterWatch, a Boston-based group that tracks the situation, the portion of this research performed in the academic sector has been cut to 40 percent, while the remaining 60 percent has shifted to for-profit firms paid by the drug industry, which increasingly contracts out clinical-trial work to physicians in private practice who have little or no training in the specialty field of clinical research. Even within the academic setting, new competitive pressures are eroding the arms-length relationship that once existed between academic investigators and their corporate sponsors.
To be sure, the pharmaceutical and biotech industries need to bring new medical advancements to the public in a timely fashion. But over time, it is FDA review and certification that protects the industry from its own excesses. With more than 100,000 Americans dying each year from adverse reactions to prescription drugs--drug reactions are the nation's fourth-leading cause of death--the last thing we need is to dismantle the few regulatory checks and balances that remain.
Hijacking the AIDS Legacy
Ironically, the impetus to reform the FDA began not with the drug industry but among grass-roots activists in the AIDS community. More than a decade ago, on October 11, 1988, roughly 1,000 AIDS activists stormed the FDA's headquarters in Rockville, Maryland, chanting: "We're the experts, let us in!" The purpose of the demonstration, which shut down FDA headquarters for a day, was to expedite the release of experimental drugs to HIV and AIDS patients (an estimated 45,000 of whom had already died in the United States). The action was successful, prompting the FDA to implement a series of reforms that enabled patients to access drugs still being tested in clinical trials.
Unwittingly, however, the AIDS activists had created an opening for the pharmaceutical industry. Seeking to capitalize on the message that drugs needed to reach the market more quickly, drug companies and their political allies began pushing for their own brand of streamlining.
In 1991, President George H.W. Bush's Council on Competitiveness (headed by Vice President Dan Quayle) called for full-scale privatization of the FDA. Citing the need to "improve the efficiency of the FDA approval process" and expedite the release of drugs for life-threatening diseases, the council recommended contracting out much of the drug-review process to private outside reviewers paid by the drug industry. Though this initiative was not enacted in that form, Congress, prodded by the drug industry, soon passed the Prescription Drug User Fee Act of 1992. This new system required manufacturers to pay a "user fee" for every new drug application submitted to the FDA and, in return, obligated the FDA to expedite its drug reviews dramatically. User fees enabled the agency to hire more reviewers and reduce review times from 31.5 to 14.5 months on average. Yet because the act also specified that industry fees could be spent only to accelerate drug reviews, it increased the volume of drug approvals without allocating new resources to the post-marketing side of the agency that tracks whether these drugs are hurting people.
The biggest overhaul of the FDA, however, came under President Clinton's leadership. Clinton had urged the agency to treat pharmaceutical companies as "partners, not adversaries" and made FDA reform a key component of his administration's "reinventing government" initiative. In 1997, Congress approved a sweeping bill known as the Food and Drug Administration Modernization Act (FDAMA). FDAMA liberalized the FDA's approval criteria, reduced the number of clinical trials required to demonstrate the effectiveness of a new drug, and further accelerated the drug-approval process. It also fully privatized the safety reviews for several categories of medical devices. What's more, FDAMA vastly enhanced the pharmaceutical industry's marketing powers. First, it abolished long-standing prohibitions against manufacturers disseminating information about unapproved uses of drugs and medical devices, even when safety and efficacy are uncertain. Second, by easing restrictions on advertising, the act fostered an explosion of prime-time television ads hawking prescription drugs like Viagra and Claritin. Studies show that the act has dramatically boosted drug sales and increased the chances that doctors will prescribe the latest brand-name drugs that patients request (as opposed to older drugs that may be cheaper, safer, and equally effective). A study published last year in Health Affairs magazine found that three-quarters of the respondents who asked their doctors for a drug advertised on TV were successful in getting a prescription for it.
The drug industry's main trade association-- the Pharmaceutical Research and Manufacturers of America (PhRMA)--frequently justifies these reforms by invoking the language of the AIDS activists. Yet many AIDS activists say the industry has cynically hijacked their message. "We realized early on that we weren't on the same side as the deregulationists in Congress," says Mark Harrington, who led the effort in 1988 to shut down the FDA and now serves as senior policy director at the Treatment Action Group, a New York organization that promotes AIDS research and patients' rights. "They were all in bed with the biotech companies and Big PhRMA, who wanted sweeping deregulation at the FDA. The AIDS activists had a different set of goals. Our goals were for the regulatory system to become more flexible and proactive, but we still wanted the agency to be rigorous scientifically."
"Industry pushed FDAMA by claiming the public needs access to lifesaving therapies," adds Gregg Gonsalves, director of treatment advocacy at Gay Men's Health Crisis in New York. "It was the AIDS rhetoric, but we were on the other side. We were saying: 'No, we want access, but we want answers too. And you are trying to erode the ability of the FDA to show that drugs are efficacious and safe.'"
Indeed, Dr. Anthony Fauci, head of the AIDS research division at the National Institutes of Health (NIH), and Dr. Robert Temple, a senior official who deals with drug evaluation at the FDA, both confirmed in interviews that all of the regulatory changes required to expedite the release of drugs for AIDS and other life-threatening conditions were implemented well before the most recent round of reforms began in 1992. "We didn't need FDAMA to expedite drugs," explains Gonsalves. "The regs were already there. It was a cynical initiative. They already had an expedited mechanism, and they were pushing for more. In the end, the industry is not going to be served when drugs get yanked off the market because somebody drops dead from taking them. And that's precisely what we are seeing today."
The Human Cost of Unsafe Drugs
In the last five years alone, eight drugs approved since these changes were enacted have been withdrawn or severely restricted because of serious side effects and deaths. The number is unprecedented. According to Public Citizen's Health Research Group, during the entire period from 1970 to 1992, the FDA approved only nine drugs that were later banned owing to safety concerns. The eight drugs lately withdrawn were GlaxoSmithKline's Lotronex, for irritable bowel syndrome; American Home Products' Redux, a diet aid; the Bayer Corporation's Raxar, an antibiotic; Pfizer's Trovan, also an antibiotic; Roche's Posicor, a blood-pressure medication; Wyeth-Ayerst's Duract, a painkiller; Warner-Lambert's Rezulin, a diabetes drug; and, this spring, Organon's Raplon, an anesthetic. With the exception of Raplon, there is evidence in all of these cases that the FDA's own medical officers and specialists voiced serious concerns about the toxicities and risks known to be associated with these drugs at the time of review--warnings that were overridden.
As FDA officials point out, drug review is not an exact science; it involves a complex weighing of risks versus benefits. Testing generally is performed on no more than 4,000 people, a sample too small to detect all the adverse reactions that may potentially arise. That being the case, whittling away at the FDA's regulatory powers and autonomy hardly seems to be the answer.
Of all the drugs recently withdrawn, none better illustrates the dangers of dismantling regulation than Rezulin. Manufactured for the treatment of adult-onset diabetes, Rezulin was withdrawn from the U.S. market in March of last year after the drug was associated with a startling 391 deaths, including 63 that involved liver failure. In the Los Angeles Times, reporter David Willman recently revealed that even as Rezulin's safety was being questioned internally at the FDA, Warner-Lambert executives received special favors from high-placed agency officials. In one internal memo, a company executive thanked Dr. Murray M. "Mac" Lumpkin, then deputy director at the FDA, for canceling a medical officer's engagement to speak publicly about Rezulin and its association with liver toxicity. Another senior FDA official, Dr. G. Alexander Fleming, offered to "ease out" a medical officer who had expressed doubts about a Rezulin safety study, according to company records.
Rezulin remained on the U.S. market more than three years after safety concerns prompted Great Britain to ban the drug in December 1997. Remarkably, one month before this ban, the FDA's own diabetes specialist, Dr. Robert Misbin, estimated that 12,350 of the 650,000 patients then taking Rezulin could be at risk for liver injury and that the complications in some 2,000 of those cases could be life-threatening. Yet while the FDA did start recommending that doctors perform increased liver tests, it continued to maintain that Rezulin's benefits outweighed the risks. Today, Warner-Lambert is facing some 383 lawsuits from plaintiffs claiming Rezulin-related injuries and deaths.
The most recent evidence of the client relationship between regulators and the industry is the FDA's attempt to bring Lotronex back on the market, despite new studies by its own epidemiologist showing that the risk of the life-threatening condition ischemic colitis is actually far greater than was thought when the drug was withdrawn last November. Leaked internal memos indicate that, as with Rezulin, the FDA's Center for Drug Evaluation and Research has been working behind the scenes to help the manufacturer--including offering GlaxoSmithKline assistance in managing the media and in structuring an advisory committee more favorable to the drug. In May, Dr. Richard Horton, the editor in chief of The Lancet, denounced the FDA's handling of Lotronex. "This story," he noted, "reveals not only dangerous failings in a single drug's approval and review process but also the extent to which the FDA, its Center for Drug Evaluation and Research in particular, has become the servant of industry."
Industry's Growing Influence over Research
Although the public by and large assumes that any drug bearing the FDA's stamp of approval has been independently tested, virtually all the safety studies the FDA reviews are conducted and paid for by the pharmaceutical companies. The system essentially relies on a strong research environment to produce reliable data that are scientifically sound. But here, too, changes over the last decade have vastly enhanced the drug industry's influence.
More than 80 percent of all clinical trails today are funded by the pharmaceutical industry, not the government. The arms-length relationship that once existed between researchers and the drug industry is eroding. "The essence of research is impartiality," explains Dr. Marcia Angell, former editor of the New England Journal of Medicine. "There is no substitute for a researcher who is disinterested in the outcome because it is too easy to bias the results either consciously or unconsciously. What we are seeing now is the disappearance of impartial researchers and institutions," she says. "As the economic ties between researchers and industry become virtually ubiquitous and manifold, you have to worry about the quality of the research."
The problem can be traced, in part, to the financial predicament facing many of the nation's nonprofit medical colleges and their affiliated teaching hospitals, which used to conduct the vast majority of drug research. Both the Balanced Budget Act of 1997, which prompted sharp cuts in Medicare reimbursements to teaching hospitals, and the rise of managed care have left academic medical centers with serious budget shortfalls. Although spending on basic research by the NIH has remained robust, universities have suffered serious losses on the clinical-research side, making them far more reliant on the pharmaceutical industry for support.
Yet beginning in the 1990s--precisely when medical colleges were feeling the financial crunch--the pharmaceutical industry opted to shift much of its clinical research to for-profit research companies known as contract research organizations (CROs) and site management organizations (SMOs). The CROs provide companies with central oversight and management of their various clinical trials, while the SMOs organize physicians' offices into trial networks and oversee the rapid recruitment of patients. Today, as a result of this diversion of funding, major academic medical centers receive an estimated 34 cents of every dollar that industry devotes to clinical research, down substantially from 75 cents per dollar in the early 1990s.
Studies indicate that commercial entities do complete clinical trials faster and more cheaply than their academic counterparts--an obvious virtue for the pharmaceutical industry, which estimates that it costs $1.3 million every day that a manufacturer is delayed in winning FDA approval. But have these changes been good for medical research and public health?
Michael Leahey, who directs the central Office of Clinical Trials at Columbia University and New York Presbyterian Hospital, notes that CROs and SMOs commonly contract out their clinical trials to physicians in private practice who, despite their medical degrees, often have virtually no training in clinical research. "The norm, the scary stuff," says Leahey, "is some doctor in private practice who is looking to augment his income yet doesn't know, or doesn't understand, what informed consent is. So he pressures patients into studies and has nurses dispensing drugs that are not properly accounted for.... It's a real danger."
Fee reductions from managed care have prompted legions of physicians to take up drug research as a means of replacing lost income. Doctors can receive anywhere from $1,000 to $6,000 for each new patient they enroll in a clinical trial, and top recruiters earn somewhere between $500,000 to $1 million a year. In 1999, The New York Times reported that doctors are bombarded with enticements from industry--"Improve Your Cash Flow," "Discover the Secret for Obtaining More Funded Studies"--which have contributed to nearly a threefold increase in the number of private physicians conducting human experiments since 1990. In its 10-month investigation, the Times uncovered numerous cases in which doctors relaxed eligibility criteria for patient enrollment in trials, fabricated data, and handed off their professional responsibilities to untrained nurses and assistants. In one case, bodily fluids that met certain lab values were stored in an office refrigerator, ready to be substituted for the urine or blood of patients who did not qualify for studies. Seventy percent of the doctors involved in these trials, the Times found, had taken part in three or fewer previous drug studies--one indication of their general lack of experience. Leahey believes that the only way to restore integrity to the clinical-research process is for medical colleges and teaching hospitals to learn to perform trials more efficiently while also preserving quality. "I have always felt that the CROs were something we could effectively compete with," he says, noting that under his management the Office of Clinical Trials launched 200 trials with a value of $40 million last year.
The Captive Academy
The trouble is, many universities and academic medical centers are themselves succumbing to commercial pressures. The Massachusetts Institute of Technology, for example, has embarked on a five-year, $15-million collaborative research venture with Merck and Company that grants the firm patent rights to any joint discoveries. Boston's Dana-Farber Cancer Institute, a teaching hospital affiliated with the Harvard University Medical School, has a similar deal with Novartis Pharmaceuticals for research related to new cancer drugs. And this February, Harvard's Beth Israel Deaconess Medical Center solicited bids from 40 companies to conduct joint research at a new medical facility.
Academic administrators say that these relationships provide professors and students with valuable research experience and much needed support. But the web of financial ties has become so pervasive that institutions and their professors are now frequently in business with their corporate sponsors--an arrangement that creates the potential for serious conflicts of interest.
The problem was brought home dramatically in September 1999 when Jesse Gelsinger, an 18-year-old boy from Tucson, Arizona, died in a gene-therapy experiment at the University of Pennsylvania. Subsequent investigations revealed that the lead scientist and the university had equity stakes in the company sponsoring the research lab--ties that were never disclosed to the patients. The scientists also improperly withheld information from regulatory authorities, including reports of serious adverse events and early studies showing that monkeys had died after receiving similar treatment.
Most human-subject research is supposed to be vetted and approved by a local Institutional Review Board (IRB), consisting of scientists and disinterested citizens, to ensure that trials are in compliance with federal research laws. But recent reports by the U.S. Department of Health and Human Services' Office of Inspector General and other government agencies have criticized the IRB system for rubber-stamping approvals and failing to protect human subjects adequately. (The problem is even worse in the commercial sector, where some industry studies are wholly unregulated and others are reviewed by for-profit IRBs paid by the drug industry.)
The Gelsinger case is not isolated: Since 1999, federal authorities have restricted or shut down human-subject research at nine universities--a troubling sign that scientific standards in academia may be eroding. "The boundaries between the academic medical colleges and the drug companies are becoming ever more porous," says Marcia Angell. "It used to be that academic medical colleges said, 'Okay, we will take this grant and do the study, but our researchers are going to design the study, they are going to retain the data, they are going to analyze the data, and they are going to write the paper.' Now this arms-length relationship has broken down."
Indeed, in a May 2000 article published in the New England Journal of Medicine, Dr. Thomas Bodenheimer, an internist and a professor at the University of California at San Francisco (UCSF), highlighted the variety of ways that corporations can control and manipulate clinical trials to suit their interests. Bodenheimer found extensive evidence of study-design bias (the sponsor's drug, for example, is given in higher dosages than the competing drug); publication bias (a tendency among corporate sponsors to publish only results that are favorable); even ghostwriting (wherein companies pay scholars to add their names to journal articles written by corporate marketing departments).
Bodenheimer says that companies now frequently retain control over the raw data from a clinical trial, a practice that makes it far easier to spin the results. "Some principal investigators have the capacity to analyze all the data from a large trial," he explains, "but companies prefer to retain control over this process." An executive at one company told him: "We are reluctant to provide the data tape because some investigators want to take the data beyond where the data should go."
Dr. James Kahn, an AIDS researcher at UCSF, recently confronted this problem firsthand. In 1999, when he and a Harvard University biostatistician, Dr. Stephen Lagakos, attempted to publish new research showing that an AIDS therapy was ineffective, their corporate sponsor, Immune Response Corporation, tried to block publication. According to the researchers and UCSF, the sponsor refused to release the complete trial data. Still, Kahn and his colleagues pressed ahead with what they estimate was 95 percent of the critical data set and published an article in the Journal of the American Medical Association (JAMA) last year. Immune Response, in turn, slapped Kahn and the university with a $10-million arbitration claim, alleging that they had defamed its product.
Of course, what companies like Immune Response want are studies that reflect positively on their products. And much of the time, this is what they get. A recent study published in JAMA found that nonprofit studies of cancer drugs were eight times more likely to reach unfavorable conclusions than industry-sponsored studies. Another, by Mildred Cho, a scholar at Stanford University, revealed that 98 percent of papers based on industry-sponsored research favored the drugs being examined, as compared with 79 percent of studies based on research not funded by industry.
Several prominent academic physicians interviewed for this article expressed another concern: namely, that overdependence on pharmaceutical funding is skewing the research agenda. Because pharmaceutical companies look to fund research that is commercially profitable and the NIH primarily finances basic medical research, clinical investigators studying rare diseases, third-world epidemics, or adverse reactions caused by existing drugs are hard-pressed to find support.
According to Dr. Leon Eisenberg, an emeritus professor of social medicine at Harvard, "Doing the 14th trial on an 18th-generation antibiotic is not like doing fundamental research in the laboratory, but it is potentially profitable. So there is a certain diversion of energy--this business of making money to keep afloat. It does have a negative effect on medical colleges." Of particular concern to the FDA, former Commissioner David A. Kessler has written, is industry-sponsored research that is purely market driven and has "little or no scientific purpose." In some studies, known as "seeding trials," the sole purpose of the "research" is to get doctors to switch patients over to a new drug therapy. And in 1998, The Wall Street Journal found that a full 25 percent of patients in clinical trials are enrolled in post-market studies that are primarily designed to secure a company's market position after a drug has been approved.
"We already have many Claritin-type drugs for allergies," says Angell. "How many do we need? They are all very similar, but what is happening is that the drug companies focus their resources on marketing 'copycat' drugs to convince doctors and patients that somehow theirs is better than all the others." For Angell this emphasis on marketing as opposed to new therapeutic discovery is troubling. "It is very hard to justify enrolling human subjects in a trial if the trial is fundamentally trivial," she explains. Clinical trials are very important, she adds, "but I don't believe we should waste the time and energy of talented researchers or the altruism of human subjects."
The Need for Oversight
Given the unprecedented influence that the pharmaceutical and biotech industries now wield over clinical drug research and the FDA, the need to bolster--not reduce--federal regulations is urgent. Contrary to what The Wall Street Journal's editorialists claim, there is no evidence to suggest that the medical-research pipeline is being squelched by excessive government interference. Industry investment in research and development is strong, new-drug approvals are up from 70 in 1993 to 98 in 2000, and the average drug-approval time has been cut in half. The real problem is that the FDA is rapidly losing its ability to function as an autonomous agency.
When the prescription drug user fee act comes up for reauthorization next year, the drug industry is widely expected to push for further deregulation. Congress should remain firm. It should reinstate laws thrown out in 1997 that restricted TV advertising and limited the promotion of unapproved, "off label" drug uses. It should also increase the FDA's post-marketing budget so that the agency can properly respond to serious adverse reactions that arise after drugs come on the market. While efficiency is important, the FDA ought to focus more on the quality of its reviews and avoid conflicts of interest by making sure that its front-line medical officers and advisory committees are operating free from industry influence.
Safeguarding the nation's drug-research infrastructure will also require that government play a stronger balancing role. The NIH could help counter the dominance of industry-research money by assigning a larger share of its grants to less-commercial areas of clinical research, which academic investigators are uniquely qualified to pursue.
Human subjects also deserve better protection. The same HHS Inspector General report that declared the IRB system "in jeopardy" also criticized the general lack of federal oversight over clinical research, noting that "it is time ... for a fundamental re-examination and re-engineering of the HHS oversight process." Both the FDA and the NIH need more staff and resources to conduct unannounced on-site inspections of clinical trials in progress and the power to impose financial penalties when they find violations. And federal laws protecting human subjects should be extended to all commercial research.
Given the current political climate in Washington, the pharmaceutical industry and its allies in Congress will undoubtedly resist efforts to strengthen government regulation. The Senate, at least, can use the power of committee oversight, now back in Democratic hands, to probe issues that Republican senators have long swept under the rug. Massachusetts Senator Ted Kennedy--the new chairman of the Committee on Health, Education, Labor, and Pensions, which has oversight over the FDA--should begin by immediately calling for a series of hearings on the large number of drug withdrawals over the last five years (this may also merit an independent congressional audit); the inadequacies of the agency's post-marketing surveillance system; and the public-health consequences of mass prescription-drug advertising. The committee can also fulfill its oversight responsibilities by carefully re-examining the Prescription Drug User Fee Act before it comes up for reauthorization next year. The law's "user fees" have made the FDA beholden to the drug industry for much of its funding and, many believe, have encouraged the agency to treat pharmaceutical firms more as clients than as a $100-billion industry to be monitored and regulated.
As committee chair, Kennedy's committee also makes the initial determination whether to approve or reject Bush's choice for FDA commissioner, since Senate confirmation is required. Kennedy seems poised to use his position to ensure that the next commissioner is truly independent. "To my knowledge," says Sidney Wolfe, director of Public Citizen's Health Research Group, "in my 30 years working on this issue we have never had an FDA commissioner who came from industry." But that could change: Shortly before TAP went to press, Bush staffers floated Michael J. Astrue's name as a likely choice to head the agency. Astrue, general counsel of Transkaryotic Therapies, has strong ties to the pharmaceutical industry. Reports of his incipient nomination prompted Kennedy and six other health committee Democrats to write Bush warning of political fallout should the president break with precedent and appoint an industry insider to head the FDA.
In the long run, neither the drug industry nor the public will be served if the integrity of the American medical system and the FDA's drug-review process are undermined. The alarming number of clinical-research abuses that have come to light in recent years--both in private and in academic settings--signals that researchers must be held to higher standards. Medical researchers depend on the altruism of human volunteers to bring new drugs to market. If the federal government and the scientific community don't act now, they may discover, too late, that the public trust is hard to win back.
