February 22, 2001
Tommy Thompson
Secretary
U. S. Department of Health and Human Services
200 Independence Avenue, S. W.
Washington, D. C. 20201
Fax: (202) 690-7203
Dear Secretary Thompson:
We have learned that the Food and Drug Administration (FDA) is seriously considering endorsing the design of a drug-company study of a new surfactant drug in four Latin American countries in which a control group of 325 premature newborn infants with potentially fatal Respiratory Distress Syndrome (RDS) would be treated with placebos instead of a lifesaving and already FDA-approved surfactant drug. In a clear demonstration of the exploitive nature of this proposed research, the same manufacturer that is seeking approval for this drug plans a study in Europe in which all infants not receiving the new surfactant drug will receive an already FDA-approved surfactant drug. Internal FDA documents state that "Conduct of a placebo controlled surfactant trial for premature infants with RDS is considered unethical in the USA."
Surfactants like the drug to be tested here have been shown to reduce neonatal mortality by 34%[1] and the FDA estimates the neonatal (28-day) mortality rate among premature infants in these countries to be at least 30%. If half of the infant deaths were due to RDS (this was the case in the U. S. in the pre-surfactant era)[2] the provision of placebo (instead of another form of surfactant) to the 325 infants in the control group will result in the preventable deaths of 17 infants (325 X 0.3 X 0.5 X 0.34).
Particularly because the FDA approved another surfactant (Infasurf) in 1998 on the basis of studies performed between 1991 and 1993 in which all infants were treated with a presumably effective drug and none were given placebo, we call on you to immediately put a stop to plans for this unethical and exploitive study in its present design. The study is unethical because it violates the principle that placebos not be employed when there exists a standard treatment that may reduce or prevent harm, improve health or prolong life. If the study produces findings that are beneficial to patients in wealthier countries but the drug is not widely available in the countries in which it was tested, an additional dimension of unethical behavior will have been added. For the study to take place ethically, all infants must be provided with a treatment either known or expected to be effective; a comparison of the new surfactant to an already approved one would therefore be acceptable.
The information on the trial we present here is based on documents (see attached ) made available to hundreds of FDA employees in conjunction with an internal FDA Scientific Rounds on January 24, 2001. The meeting had the extraordinarily inappropriate, but revealing, title "Use of placebo-controls in life threatening diseases: is the developing world the answer?" As noted, information presented by the FDA at the meeting acknowledges that "Conduct of a placebo controlled surfactant trial for premature infants with RDS is considered unethical in the USA." Moreover, in the countries where the trial would take place (Bolivia, Ecuador, Peru and Mexico), surfactants are used in some hospitals, but "surfactants are completely unavailable to infants at many other hospitals, secondary to rationing or economic limitations," the FDA documents say. It is in these latter hospitals that the studies are planned. The cost of a course of surfactant for a 1500g premature infant is estimated to range between $1079 and $2440 (Average Wholesale Prices; personal communication, Tony Mavrantonis, Medical Economics, February 15, 2001). Because the drug is still an Investigational New Drug, neither the name of the product nor that of the manufacturer is available to us.
Respiratory Distress Syndrome
RDS is a common condition in premature infants. In 1998, 1328 U. S. infants died of RDS, making it the fourth largest cause of infant mortality.[3] Historically, approximately 50% of all neonatal deaths resulted from RDS,2 although with the advent of surfactant this percentage has decreased greatly. However, the 50% figure is probably still a reasonable estimate for areas without access to surfactant or neonatal intensive care. Annual incidence is estimated at 60,000-70,000 cases in the U. S.[4] The condition occurs in 60%-80% of infants under 28 weeks gestation and in 15%-30% of those born between 32 and 36 weeks.[2 ]
In a major scientific breakthrough in the 1960s, scientists discovered that one key cause of RDS is a deficiency or dysfunction of a naturally occurring chemical called surfactant. Surfactant reduces surface tension in alveoli (small air sacs) in the lung. In the absence of functional surfactant, markedly increased pressures in the alveoli are required to inflate the lungs, preventing proper aeration. In the 1970s and 1980s, scientists worked to produce a safe and effective surfactant that could be instilled in the lungs of premature infants to reverse the devastating course of RDS. The first surfactant (Exosurf) was approved in the U. S. in 1990, the second (Survanta) in 1991, the third (Infasurf) in 1998 and the fourth (Curosurf) in 1999. Exosurf is a synthetic compound, Survanta and Infasurf are isolated from cow lungs and Curosurf is isolated from pig lungs. All are administered while the infant is receiving advanced life support; the liquid surfactant is instilled down the endotracheal tube, generally with the infant sequentially in four different positions to maximize dispersal of the liquid. Infants often respond within minutes. Surfactant may be administered shortly after birth, before the infant develops respiratory distress; this is known as prophylactic therapy. Alternatively, the clinician may wait to see if respiratory distress develops and, if it does, administer surfactant; this is known as treatment or rescue therapy.
Clear Evidence that Surfactant Saves Newborn Lives
Multiple clinical trials attest to the efficacy of both synthetic and natural surfactants in reducing neonatal mortality. For this reason, surfactant was described in an article in the New England Journal of Medicine as long ago as 1993 as "without doubt the most thoroughly studied new therapy in neonatal care" and as "a major advance in neonatal care."[5] By then, there had been 35 randomized, controlled trials (most with placebo) which together demonstrated efficacy in reducing neonatal mortality for both natural and synthetic surfactants for both prophylaxis and treatment of RDS.
To assess the current state of knowledge regarding surfactant efficacy, we consulted the Cochrane Library, an ongoing international collaborative effort among scientists to collect and synthesize the results of all clinical trials for a large number of conditions using a statistical technique called meta-analysis. There have been seven Cochrane reviews involving surfactant, each including about seven separate clinical trials. There is some overlap between the reviews. These include studies of prophylaxis and treatment of RDS as well as studies of natural and synthetic surfactants. Because the surfactant to be tested in the proposed study is a synthetic surfactant and because the FDA documents indicate that this is a treatment trial, we have paid most attention to the review comparing synthetic surfactant to placebo for the treatment of RDS.[1 ] (In these studies, "placebo" generally means the administration of "sham air" rather than surfactant down the endotracheal tube.) However, the results of prophylactic trials with synthetic surfactants are generally similar.[6] There is no Cochrane review of natural surfactant for treatment of RDS, although an earlier meta-analysis by the same Cochrane author concludes that "mortality is reduced in infants with RDS who were treated with [natural surfactant]."[7]
Six placebo-controlled studies of synthetic surfactant in the treatment of RDS in premature infants were deemed to be adequate for inclusion in the meta-analysis by the Cochrane author; all but the smallest of these involved Exosurf. The Table summarizes the results of the six studies. The studies evaluated a number of different patient outcome variables, the seven most important of which appear in the Table. Not all studies evaluated all outcomes. For each of these outcomes, at least one (and often more) of the studies reached statistical significance (surfactant was significantly better than placebo), although different outcomes were statistically significant in different studies.
The probability of finding a statistically significant result for a given outcome was strongly related to sample size. The largest study[8] ,[9] ,[10] had a total of 1237 patients in two arms and five out of seven outcomes showed statistically significant beneficial effects for surfactant. The smallest study[11] included only 24 patients and, not surprisingly, showed no statistically significant finding for any of the three outcome variables it evaluated. Importantly, all but the largest study are smaller than the study proposed here (and so "false-negative" results are less likely); the five smaller studies account for 22 of the 24 non-statistically significant findings. The failure of small studies to show statistically significant findings that would be apparent if all studies were combined is the very rationale for meta-analysis.
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