HPV vaccines. The enquiry set up by the government confirms our worst fears

HPV VACCINES. THE ENQUIRY SET UP BY THE GOVERNMENT CONFIRMS OUR WORST FEARS

Newsletter Jan-Aug 2011

Background

Two HPV vaccines have been in the international market since 2006. These were developed by the National Cancer Institute, USA. The reasoning was, that of the more than hundred known subtypes of Human Papilloma Virus, fifteen were found to be associated with cervical cancer. And a vaccine could bring down the incidence of cancer if the most prevalent cancer related subtypes were covered by it. Accordingly, a vaccine was developed to prevent infection with subtypes 16 and 18 associated with 70% of cervical cancer cases. This technology was transferred to Merck, which developed a vaccine called Gardasil and to GlaxoSmithKline, which developed another called Cervarix. In 2006, when Gardasil was approved in the US for females in the age group 9-26 yrs, there was insufficient data about its efficacy and safety among adolescent girls, hence the USFDA had specifically asked Merck to keep track of the health of the adolescent girls getting these vaccines. It had also asked the company to carry out further research to demonstrate that the vaccines actually led to a fall in cervical cancer cases and that the remaining thirteen subtypes (not included in the vaccine) did not take the place of 16 and 18 thereby leaving cancer incidence untouched. As the vaccines covered only 70% of HPV infections, continued screening for cervical cancer remained a requirement. Also, as these vaccines had no effect on women who were already infected by HPV, and as the virus is largely sexually transmitted, the strategy was to vaccinate young girls.

At Rs 9,000 for a three dose regimen, these vaccines were among the most expensive vaccines in the world. Despite this fact, they were sought to be introduced in the third world including India.

In 2005, Merck signed an MoU with ICMR even before Gardasil was approved in the home country (US). In June 2006, soon after USFDA approval, the Bill & Melinda Gates Foundation gave a large grant to PATH, a US based NGO, to expedite introduction of HPV vaccines for research in four third world countries. India was one of them. In 2007, PATH signed a MoU with ICMR for their Evidence for Impact Study and together they first carried out a formative research with a view to understanding behavioural and attitudinal issues among potential vaccine receivers, villagers, health workers as well as policy makers in Gujarat and Andhra Pradesh. The villagers raised concerns about whether the vaccines are safe/government approved and wanted additional assurance that the fertility of the recipients would not be adversely affected. The research also looked at the governmental health system in the two states to assess their ability to report adverse events associated with vaccination which showed up to be highly inadequate. The formative research also had a third objective – objectionable as far as we are concerned - as it involved making a successful lobbying strategy that would result in a favourable decision to introduce the vaccine in India.

As per the MoU between ICMR and PATH India, a demonstration project was also planned following the formative research. Though ICMR wanted to undertake safety and efficacy trials, these vaccines got approved by the Drugs Controller in 2008 without adequate research. After that the companies engaged in unprecedented marketing efforts and promotion. ICMR’s plans for trials were also pushed aside. Even the Phase III trial with Gardasil started only after licensing and Cervarix was never tested among Indian adolescents.

PATH-ICMR Vaccination Project – The project under enquiry

In July-August 2009, the press reported that a PATH supported demonstration project was underway in Khammam and Vadodara. This project was to vaccinate 32,000 girls in the two states. Opposition to the vaccines came from a range of groups and organisations. For six months the government did nothing. SAMA and Janwadi Mahila Samiti did a fact finding in Khammam and the media also picked up the issue. Deaths were reported and so was the unethical manner of taking consent from minors without the consent of their parents.

Finally, in April 2010 after the issue was raised in the Parliament, the government halted all trials with HPV vaccines and set up an enquiry committee to investigate the deaths and also to look into issues of ethics relating to consent in the PATH study. The committee comprised of three doctors directly under the government, and not specific experts in either the subject or in law. Though the opposition was not limited to the PATH project alone and also dealt with inadequate research before licensing, unethical advertising and many other issues, these were not included in the terms of reference of the enquiry. No representations for improving the scope and the nature of the enquiry were entertained. The committee was to submit its report in 3 months, i.e. by end July 2010. The interim report of the enquiry committee became available in February 2011. The final report was also submitted at that time However, they are not available in the public domain. We managed to get copies from SAMA though the annexures running into thousands of pages are still not available in the public domain.

overall shortcomings of the enquiry

The enquiry committee has had a one sided approach in the matter. It was set up in response to protests issues raised by women’s and health groups from all over the country, and discussions in Rajya Sabha, but did not deem it fit to include any information contained in various complaints and memoranda, it did not consider it worthwhile to have a dialogue with the ‘study subjects’ or their parents. Instead it gave three months to the accused to prepare their case and gave them all benefit of doubt. It did not take cognisance of violations relating to consent being taken on false grounds and with false claims, it did not relate the findings of the formative research with the design of the demonstration project. It did not compare the prescribing information provided by the manufacturers with what was hidden from the trial subjects. It did not even look at gross contradictions in the statements made by various actors at different places.

To give a few examples:

1. The enquiry committee report states that “It needs to be highlighted that four out of the five primary outcome measures in the study relate to evaluation of safety of the vaccine. In contrast the official website of PATH says “It should be noted that the post-licensure observational studies in Andhra Pradesh and Gujarat do not seek to evaluate the efficacy or safety of these licensed, approved HPV vaccines.” In its reply to the National Commission for Protection of Child Rights the AP government has made the same assertion about not looking at safety and efficacy of the vaccines.

2. The committee report contradicts itself. On page 5 it states very clearly that “Considerable time and effort has been invested in getting all the approvals. But the same cannot be said of its actual implementation. In hindsight the committee has identified several deficiencies in the planning as well as implementation of the project which led to the crisis requiring suspension of the study.”

On page 11, its stance changes and the crisis causing deficiencies suddenly turn into something much weaker. “Secondly, due diligence on the part of the PI (PATH), ICMR and the state governments of AP and Gujarat, the three parties involved with the project seem to have been exercised in the planning and implementation of the project… (deficiencies)... do not appear to be wilful or fully anticipable… should be taken as learning experience.”

Findings in the final report

What is striking about the final report is that the enquiry committee brought in three senior medical experts in the disciplines of Pharmacology, Paediatrics and the Dean of the All India Institute of Medical Sciences to assess the data which was found too voluminous for the enquiry committee to go through.

The criticism of these experts is scathing. According to them:

1. Regardless of the nomenclature adopted by the implementing agencies, the study was a clinical trial. Using routine reporting system of the Universal Immunization programme to record adverse events and thereby the safety of the vaccine was grossly insufficient. In fact, the minor adverse events reported are very low as compared to the other trials done with the vaccine in question giving rise to the hypotheses that this would apply equally to serious adverse reactions. Even though licensed these are new drug entities requiring four years of close follow up.

2. Forms for informed consent showed gross irregularities with missing signatures and dates. The experts took objection to the use of students as subjects in the trial as they are prone to undue pressure from their teachers. There was serious note taken of AP government circular asking principals and teachers to sign as legal guardians – a role they can play with emergency treatment for a student but definitely not for the purpose of giving an elective injection to a student as a part of a trial.

3. Serious note was taken of not following exclusion criteria set out in the research design requiring enrollment of healthy girls without allergy.

About the 7 deaths that occurred in the course of the study, the experts stated that only in two cases post mortem had been performed which established cause of death as unrelated to the vaccine. The rest of the cases were also declared as unrelated even though they were not dealt with properly, with neither the treatment regimen nor the accompanying symptoms recorded.

As per the final report despite asking, the enquiry committee was not provided financial details about the PATH study, but the final report glosses over this. Yet what is clear in the report is that NRHM (National Rural Health Mission) funds were used for the study.

However, the report has acknowledged that the distinction between the regular immunisation programme and research was blurred. The report has also drawn attention to the fact that in getting vaccines free of cost from the two companies does raise concerns about undeclared conflict of interest since the results of the study may be used to influence the decision by the government.

The next startling revelation is a casual mention that the eligible age group for Gardasil had been extended from 9-26 years to 9-45 years. This fact is of grave importance as in US, the home country for Gardasil, Merck’s application for extension to older women has been turned down thrice. Also Merck has been forced to acknowledge that its vaccine has no beneficial effect on women older than 26 years.

The enquiry also found PATH had insured itself while the research subjects were left to fend for themselves.

Our critique of the report:

According to us the enquiry has fallen short of full investigation and on fixing responsibility on many important counts.

1. The true sequence is that these products have been licensed without proper trials among the age groups they are being prescribed for. Then this improper licence has been used to shield fraudulent and criminal conduct. False information has been given to users and their guardians in the Indian package insert. The guardians have been bypassed whenever convenient. A vaccine meant exclusively for healthy girls and women has been administered on a population based in remote blocks of backward districts without even a proper health check up. The vaccines have been tried on children without first going for trial among adults, and this practice of waiving adult trials has been justified by taking the commonality of this violation as a shield in the report “there are several exceptions to the general principle which provide trial to be carried out in children in special circumstances”. Adverse events have not been noted and even deaths came to light only when the next dose was to be administered. In fact, recording of adverse events was left to routine reporting despite PATH’s formative research having shown that this was grossly insufficient. Post mortems were waived off against all good practices and the word of the doctors who had waived it was taken as the gospel truth to conclude that ‘deaths are not related’ to the vaccine.

2. The enquiry committee has missed the wood for the trees, and that too, its thin outlying branches! It has stopped short of looking at the licensing. It has failed to note that no trials were done with Cervarix among children in India before the Gujarat project. Hence it has made the mistake of saying that licence included minors and so there was nothing wrong in doing the PATH trial with children. Instead of noting this as a deficiency of the Drugs Controller, who first gave licence for this age group without trials and then permission to the PATH project, the enquiry committee has cited other drug authorities and professional associations to establish product safety. If this indeed is the case why do we need our own laws, authorities and research agencies?

3. While the report has raised one issue of conflict of interest, there is another one that has been missed out. This relates to Bill and Melinda Gates Foundation. In 2006 when PATH was funded for this exercise, the foundation had substantial share holdings in Merck.

4. If we look at the findings of PATH formative research it is clear that the blurring of distinction between the project and NRHM was deliberate. All the project literature actively used NRHM logo which satisfied the villagers who were ready to accept the vaccine provided it was given by the government.

5. The report has failed to work out the number of incomplete vaccinations given in the PATH study. In analysing the information for Gujarat (that we obtained in response to our RTI application) even our partial analysis shows that at a very generous estimate the project succeeded in giving only two thirds of the participants all three injections.

Who is responsible?

After seeing the report it is clear that the responsibility for various lapses can be fixed with various persons. For instance, as the project in-charge, Dr. Martha Jacob of PATH is responsible for all the false propaganda and using different ways of securing the so-called informed consent. Various ethical committees are responsible for noninsurance of participants, not ensuring that only healthy girls were recruited for the study and not monitoring the project.

The Drugs Controller must answer how he approved the protocol when the information being given to participants was patently false and contradicting the package insert approved by him.

Where we disagree totally with the enquiry panel is regarding their assertion that the deficiencies are minor in nature. How can violation of rights of 24,000 girls be a minor matter? How can printed misinformation overstating benefits and hiding known problems of the vaccines be a minor offence? How can death and debility arising from bio-medical research not even be monitored, treated and compensated? How can these be ignored in the context of licences which have been granted without Phase II and Phase III trials considered necessary by ICMR itself?

According to us the enquiry panel is correct in stating that no one agency could be held entirely accountable for the lapses. But the lapses are serious and the case must be put before a competent legal authority to assess the damage and provide for medical attention and compensation to the trial subjects with costs to be recovered from the government, PATH, Bill and Melinda Gates Foundation, Merck and GlaxoSmithKline. It is a matter of criminal and financial liability.

The positives of the enquiry are:

• It has asked for scientific and ethical re-review of all other studies planned or underway with the HPV vaccines.

• It stressed that everyone should desist from research on tribal population, unless it is of specific benefit to them.

• It has said that insurance cover should have been given.

• It has recommended strengthening procedures to assure safety of study participants.

• Above all it has asked for making a unified statutory law to safeguard the interests of the subjects

In a joint memorandum with other groups we have raised many of these matters with the Ministry. Now we need to campaign to make sure that our critique gets due attention.