Question of ethics

The effectiveness of the HPV vaccine in preventing cervical cancer was tested without proper consent from vulnerable subjects.

EARLY last year, an ambitious, population-based, post-licensure study of the effectiveness of the human papillomavirus (HPV) vaccine to prevent cervical cancer conducted in selected districts of Andhra Pradesh and Gujarat by PATH, an international non-governmental organisation, ran aground following the death of seven girls. The conduct of the study has now come in for much criticism from a government inquiry committee constituted to look into it. It has drawn flak mostly for deficiencies in obtaining consent in the case of vulnerable groups. The report is not yet in the public domain.

India is said to have one-fourth of the world's cervical cancer patients, and PATH initiated a five-year project to advance the prevention of the disease. The three-phase study was done in collaboration with the Indian Council of Medical Research (ICMR) to generate evidence that would enable policymakers to decide on possible public sector introduction of the HPV vaccine. The Rs.250-million project, titled HPV Vaccine: Evidence for Impact, was funded by the Bill and Melinda Gates Foundation. The vaccine for the project came as donations from GlaxoSmithKline and Merck Sharp & Dohme. The project had all the approvals from the designated agencies.

The objectives of the study were threefold: to demonstrate suitable HPV vaccine delivery strategy for 10- to 14-year-old adolescent girls; to raise community awareness of HPV, cancer of the cervix and its prevention; and to gain experience in HPV vaccination and to build the evidence base of vaccine delivery strategies for the future introduction of HPV vaccine in the universal immunisation programme. The target group of the demonstration project was 16,000 girls in three blocks each in Khammam district in Andhra Pradesh and Vadodara district in Gujarat.

The project was carried out in a public-private partnership (PPP) model with the approval of the two State governments, with the ICMR involved in it from the beginning as an adviser and facilitator. The vaccination started in Khammam in July 2009 and in Vadodara the following month. As many as 14,091 girls in Khammam were given the first dose of the vaccine, 13,930 the second dose and 13,791 a third dose. The corresponding numbers in Vadodara were 10,686, 10,259 and 9,637.

The project attracted wide attention in the media following the death of seven girls (five in Andhra Pradesh and two in Gujarat), and the Central government decided to suspend the study. On April 15, 2010, a four-member (later reduced to three) committee was constituted to look into the alleged irregularities in the conduct of studies using HPV vaccine by PATH in India. The committee comprised Professor S.P. Agarwal, former Director-General, Health Services, Ministry of Health and Family Welfare and current Secretary-General of the Indian Red Cross Society; Dr Suneeta Mittal, professor and head of the Department of Obstetrics and Gynaecology, All India Institute of Medical Sciences (AIIMS); and S.S. Agarwal, former Director, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow. The committee was further assisted by three experts. Early this year, the findings of the interim report of the committee were selectively leaked to the media. The final report, which was out in February, is yet to be placed in the public domain. It is interesting to note that though the inquiry committee did not find any link between the deaths and vaccination, it found lapses as far as protocols of clinical trials and ethical issues of consent, particularly in the case of vulnerable groups, were concerned.

The committee has come out with many damaging conclusions, which throw light on the manner in which health care and the financing of projects under PPP arrangements are managed in the country. A copy of the report is available with Frontline. The report says: It is important that public private partnership programmes be extra vigilant and ensure that the authority of the state is not misrepresented.

The committee has made several observations about the socio-economic profile of the target population, the manner in which blocks where the study was to be conducted were chosen, and the standard of medical care in the areas under study. For instance, the percentage of tribal girls selected for vaccination was higher than the national or state average. While on one hand, difficult to reach and (a) more socio-economically backward population may be [a] more deserving target population for HPV vaccine prophylaxis, but for better understanding of the research nature of the study and its impact on cancer prevention, a higher strata/better educated/better aware population inclusion might have been more desirable, the committee observed.

The vaccine was administered through a camp approach in schools and hostels. The inquiry committee has questioned the legality and morality of the Andhra Pradesh government in authorising hostel wardens and headmasters to sign the consent on behalf of minor girls. The report says that everyone should desist from research on tribal populations unless it is of specific benefit to them. Further, in the case of the deaths, the committee found that the reporting system as per the vaccine surveillance rules of the Government of India was not followed. According to the autopsy reports, two of the five girls in Andhra Pradesh died from poisoning and a third from drowning (all three within 45 to 49 days of receiving the last HPV dose). A fourth girl died from causes unrelated to the HPV vaccine and one from malaria. In the case of the girls from Gujarat, one died from malaria and the other from a snakebite.

There apparently was no uniformity in reporting systems and no proforma to monitor the AEFI (Adverse Event Following Immunisation), nor was any follow-up done on the deaths, the report notes. The committee noted as unusual that for such a large observational study, there was no diary card-based information record for assessing minor or major AEFI in the study protocol. Neither was there any insurance cover for the treatment of the vaccinated girls irrespective of their illnesses, the committee noted. This is when PATH took an insurance cover for itself.

The committee recommended that there was a need for a specific and separate legislation covering all aspects of Biomedical and Health Research involving human participants and eliminating overlaps such as definition of clinical trial/clinical research that exist in Schedule Y of the Drugs and Cosmetics Act Rules, GCP [Good Clinical Practice] guidelines, ICMR guidelines, etc. and that are likely to come in the future. It shall be made clear that any research involving human participants by whatever name it is called shall adhere to the directions given by this legislation, the committee stated.

Role of ICMR

In a letter to Union Minister for Health and Family Welfare Ghulam Nabi Azad, Rajya Sabha member Brinda Karat pointed out the extremely questionable role of the ICMR in the entire episode. She said the ICMR representative and some of its officials acted as partisans of PATH and the interests of the manufacturing companies.

The ICMR, which was represented in the Project Advisory Board and was a partner in the project, was also assisting the inquiry committee. She said it was unwise to allow an institution such as the ICMR to go in for the PPP mode as there was a conflict of interest.

Brinda Karat, who is a Polit Bureau member of the Communist Party of India (Marxist), had raised this issue in Parliament earlier. She also questioned the timing of the memorandum of understanding signed between the ICMR and PATH when the former had in 2007 committed itself to advising on plans for results dissemination to support decision making for the use of the HPV vaccine. How could, she asked, have the ICMR committed itself to a decision on the use of the vaccine even before the vaccine was licensed for sale in India in 2008?

Brinda Karat also pointed out that despite the Drugs Controller General of India (DCGI) demanding the submission of clinical trial reports, the ICMR supported the contention of PATH that it did not require to observe the various clinical trial protocols, including reporting on serious adverse events (SAE) within a specific time frame of the vaccination period. She asked why the DCGI remained silent when its own instructions were ignored.

At a press conference in New Delhi on May 9, Brinda Karat, along with public health experts N.B. Sarojini of the Jan Swasthya Abhiyaan and Sama, Amar Jesani of the Anusandhan Trust, and C.M. Gulhati, Editor, Monthly Index of Medical Specialists, demanded action against the NGO and full accountability from the DCGI for having approved and licensed such a study.

Expert assessment

The three experts assisting the inquiry committee have been more scathing in their assessment of the deficiencies in the study. One of them, Dr Y.K. Gupta, head of the Department of Pharmacology, AIIMS, pointed out that though PATH's project had claimed it to be an observational study, what was carried out were clinical trials in the form of demonstration projects. He observed that the study had been conducted in a vulnerable population comprising minor girls, including tribal girls.

He expressed the doubt whether the auxiliary nurse midwives (ANMs) and health workers were able to handle SAEs, including seizures and cardiac arrest, at the site of vaccine administration. In two cases of SAEs encountered during the study in Gujarat, Dr Gupta said, the details of case identities, vaccine, rescue medication and adverse events were missing. Also, in one of the deaths that occurred, no post-mortem report was attached. The SAE-reporting timelines were seldom adhered to, and in one of the deaths the report did not mention the site of the snakebite or the presence of fangs or local wound conditions. The causality assessment, Dr Gupta noted, was therefore difficult.

The five deaths that occurred in Andhra Pradesh were not properly recorded. The format of the first information reports (FIRs) for SAEs was not uniform. In one case, there was no post-mortem; in another, the patient had probably got infected after vaccination but was not admitted to hospital owing to lack of beds; and in a third, there was a dispute on the nature of the poison consumed by one of the girls. Dr Gupta observed that this indicates a need for improvement in understanding insecticide poisonings by medical officers involved.

In the case of the death from drowning, he concluded that in the absence of incomplete case records it is difficult to establish or rule out with absolute certainty [any] association of the event with the vaccine. He observed that the demonstration project may be considered a clinical trial but it did not fit the classical description of a controlled clinical trial where rigorous patient-monitoring mechanisms were usually deployed.

The timely reporting of SAEs, noted Dr Gupta, should have been taken more seriously and reported to the ethics committees. The experience, he noted, emphasised the need to strengthen pharmacovigilance at all levels of the health care system.

Further, a numerical analysis of 100 consent forms in Andhra Pradesh and Gujarat showed that signatures of the witnesses were missing in 69 forms.

The project was supposed to submit six monthly progress reports to the ICMR, but this was not done, observed Dr Rani Kumar, Dean, AIIMS. She observed that neither proper procedure of information about the HPV vaccine was followed as in remote places of AP it was done on phone or village messengers, nor consent statements followed properly. Consent forms were carelessly filled, were incomplete and probably inaccurate, and thus it was not clear how ethical it was to have vaccinated such girl participants, Dr Rani Kumar observed.

The third expert, Dr A.K. Datta, head of paediatrics, Kalawati Saran Hospital in Delhi, noted that the reporting of non-SAEs was grossly underrepresented.

This raised questions about the accuracy of SAEs as well. The delays in recording, reporting and investigation of deaths could have been because of the sole dependence on the routine state mechanism even in a research study. He said this was a significant lapse in the execution of the study.

The inquiry committee also drew attention to issues of insurance coverage, proper protocols for obtaining assent, misleading statements that could be interpreted as inducement and indirect coercion in the consent forms, and matters of PPP. The partnership of the State government in the project led to the blurring of the distinction between the national immunisation programme as routine service activity versus the research nature of the HPV vaccine project... this should serve as a lesson for public-private partnership programmes in future, the committee noted.

It has recommended that in all investigational studies, particularly those dealing with the administration of new entities, monitoring, reporting and investigation of all adverse events non-serious, serious or deaths should be an integral part of the study and the responsibility of the investigator.

The project, funded by the Bill and Melinda Gates Foundation, gave little or no information about the financial investment by the ICMR and the State governments.

The vaccine was donated by the manufacturers free of cost. At the rate of Rs.3,000 a dose, the approximate cost of vaccinating 25,000 girls would have amounted to Rs.250 million, noted the committee report. It raised the question whether the State would have provided the cold chain and manpower for immunisation had the vaccine not been free. The committee observed that the fact that the vaccine was provided by the manufacturers free of cost raised concerns about the undeclared conflict of interest since the results of the study could be used to influence the decision of the government.

In this context, the committee said there was the possibility of a hidden agenda to push this prohibitively expensive vaccine in the Indian health care system, and suggested that it might have been more prudent had the National Technical Advisory Group on Immunisation deliberated on the study before its implementation. The Ethics Committee too should have looked into these aspects before approving the studies, it noted.

The committee, while underscoring the need to address the deficiencies in the implementation of the project, observed that HPV vaccination was not a replacement for the cancer cervix screening programme, but was to supplement it. However, as the vaccine was expensive, the study should have addressed issues of cost-effectiveness and the determination of competing health immunisation priorities, it said.

The committee gave permission for the third phase of operational research on the grounds that it would provide the most useful information and not involve any further vaccination. It also recommended an ethical and scientific re-review of all studies using the HPV vaccine that had been stopped following the controversy. The re-review and the restart of these studies would be in the light of the committee's observations and findings.

However, critics of the project believe that the committee has exonerated and absolved all concerned as it has not pinned responsibility on any one agency despite highlighting the serious violations involved in the study.

The government now needs to take a hard look at the recommendations in the report, especially about vulnerable groups, ethical guidelines and the much-celebrated PPP model.