The pertussis vaccine case

In 1991 a randomized clinical trial started in Gothenburg, Sweden comparing an acellular pertussis vaccine produced by Amvax against a placebo. The trial involved around 4600 infants which were randomized to either a Diphteria-Tetanus vaccine or a Diphteria-Tetanus-Pertussis vaccine. The trial was a collaboration between scientists in Sweden, the NIH in the US and the pharmaceutical company Amvax. The trial could not be carried out in the US because it was regarded to be unethical to have half the children randomized to a trial arm without an active pertussis vaccine, as the recommended vaccination program in the US, as in most countries, involved pertussis vaccination. The use of a whole cell arm was not used in this study because it would require a much larger study. In addition to this trial, a large scale safety and immunogenicity trial was started in 1993 in the US involving 3000 children of this vaccine, without a placebo arm. The results from this trial would complement the results from the phase III trial in Sweden for a product licence application to the FDA. The results were in at the end of 1994 showing about a 70% protection of the acellular vaccine.

In addition to this trial, another trial was started in Sweden in March 1992 with a target of 10.000 infants, with four arms: SmithKline and Connaught acellular vaccines, a Connaught whole cell vaccine and a DT vaccine without the pertussis component. Similarly, in Italy in September 1992 a trial was started, with an enrollment of about 15.000 children. This trial involved a SmithKline Beecham's bivalent acellular vaccine, a Sclavo's trivalent recombinant acellular vaccine, a Connaught's whole cell vaccine and DT control. Both of these trials were carried out as a collaborative study between the NIH in the US, the pharmaceutical companies, together with researchers in the respective countries.

Critics claimed that "the trials prevent thousands of infants having access to vaccine that would protect against the disease, and accused the NIH of allegedly taking advantage of researchers by tying the contract for the trials to the provision of control groups in the study. A number of European scientists reportedly opposed the requirement but the NIH insisted that the control group was statistically necessary." In Italy, Dr. Michele Grandolfo of Rome's Instituto Superiore di Sanita was one of the researchers who criticized the trial. In the US, the trials were criticized by Albert R. Jonsen, a medical ethicist from the University of Washington School of Medicine, Seattle. According to an article in JAMA, Jonsen maintained:

"The flaw in the system is the failure to keep in working order the mechanism of open public discussion of difficult cases by the Ethics Advisory Board that was set up in 1977 and allowed to lapse in 1980....If that mechanism had been in place, Jonsen argued at a meeting of the Congressional Biomedical Research Caucus held in Washington DC, these cases would have had the benefit of full public discussion before they began" ' " ' "

Pertussis vaccination in Sweden

The vaccination program against pertussis was discontinued in Sweden in 1979. This was because data indicated that the then used whole cell vaccine, which in Sweden was without aluminum, was ineffective in protecting children against pertussis. Despite the use of this vaccine from 1963 until 1979 there had been a significant increase in the number of pertussis cases in this period. The responsible authorities therefore decided in 1979 to discontinue the vaccination program against pertussis. Since children in Sweden were not routinely vaccinated against pertussis, the children in the placebo group received standard care in that country, and consequently it was felt that the trials were justified.

One should, however, note that the decision of the Swedish authorities was controversial. It was generally recognized that the vaccine the Swedes used between 1963 and 1979 was ineffective. There was the option of using any of the whole cell vaccines used in the vaccination programs in other countries. Among some physicians in Sweden there was a general scepticism toward any whole cell pertussis vaccine, both because of the side-effects and because of the uncertain protective effect. Other physicians, however, strongly argued that Sweden should use one of the whole cell vaccines that were used in other countries. In fact, they were arguing that other countries did not have the experience with an ineffective whole cell vaccine, and they argued that all parents should be told that an effective whole cell vaccine was in fact available also in Sweden should the parents want their children to be vaccinated.