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Over the past few months, a post-licensure observational study involving administration of human papillomavirus (HPV) vaccine in India, conducted as part of PATH’s global HPV Vaccines: Evidence for Impact project, has been the focus of allegations from various groups. Recently these have been covered in the press, mainly in India. As a precaution, the Government of India has decided to suspend all project HPV vaccination and to conduct an inquiry to respond to voiced concerns.

The project is being implemented by the immunization departments of India’s Andhra Pradesh and Gujarat states in collaboration with PATH, a nongovernmental organization headquartered in the United States. The study was carried out only after receiving all required approvals in India and the United States. PATH is cooperating fully with the government inquiry to assist in allaying voiced concerns.

To date, 23,500 girls have been fully vaccinated by the Ministries of Health and Family Welfare in Andhra Pradesh and Gujarat. The HPV vaccines used are licensed for sale in India (as well as in more than 100 other countries) and were donated by Merck & Co., Inc., (Gardasil®) and GlaxoSmithKline (Cervarix®). The vaccines were developed to protect against infection by HPV, which is the primary cause of cervical cancer.

Dr. Christopher Elias, president and CEO of PATH, has issued the following statement about the project:

The mission of PATH worldwide, and in India, is to improve the health of people by advancing technologies, strengthening systems, and encouraging healthy behaviors. The HPV Vaccines: Evidence for Impact project was designed to address all three of these areas. The post-licensure observational study is generating data about vaccine coverage, feasibility, acceptability, and implementation costs associated with different HPV vaccine delivery strategies. The project also assesses cervical precancer screening and treatment strategies. It was designed, in cooperation with government agencies, to assist India’s public health system in identifying the most effective and affordable strategies to help prevent cervical cancer, a disease that kills an estimated 143,000 Indian women every year.

For approval of the post-licensure observational study, PATH and its Indian collaborators worked with two ethical review committees in India and one in the United States to design study protocols and informed consent materials. PATH is confident that these procedural safeguards informed and guided all aspects of study implementation and conduct.

Specific information about the project

The objective of the post-licensure observational study is to generate critical data and experience on effective strategies for public-sector HPV immunization programs, as part of a broader cervical cancer prevention and control strategy. The project seeks to assess HPV vaccine coverage achieved, acceptability in the community, feasibility, and cost of implementing HPV vaccination through different strategies. The project also is exploring ways to increase access to cervical precancer screening for adult women following the guidelines of the Indian National Cancer Control Program. The findings will help define the most affordable, effective, and feasible screening strategies. Project results will help the Ministry of Health and Family Welfare, Government of India, with future program planning, if and when a decision is made to introduce HPV vaccine and/or to expand screening and treatment programs.

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. No biomedical outcomes are being researched; no blood or other samples are being drawn, and no therapies are being tested. The safety and efficacy of these vaccines have been documented in numerous studies and endorsed by numerous international and national regulatory agencies.

The HPV vaccines used in the project are commercially available in India and more than 100 other countries.
The vaccines used in the post-licensure observational study have been licensed by the Indian Government and are available in the market in India and in many other countries. They are commercial products approved by the Drug Controller General of India (DCGI), US Food and Drug Administration (FDA), European Medicines Agency (EMEA), and other national regulatory bodies.

The Federation of Obstetric and Gynaecological Societies of India (FOGSI) and the Indian Academy of Pediatrics (IAP) recommend HPV vaccine, as does the World Health Organization (WHO) and many other agencies. The two HPV vaccines used in the project have been prequalified by WHO.

As of December 2009, 28 high-resource countries, including the United States, Australia, and many European nations, have included HPV vaccination in their national immunization programs.

Clinical trials of both HPV vaccines were conducted in India. 
Prior to licensure (and prior to the post-licensure observational study), clinical trials of both vaccines used in the project were conducted in India among women and girls. This was a condition of licensure. Results of these trials demonstrated high immunogenicity and a good safety profile, confirming findings reported in other countries.

To date, no deaths have been causally associated with HPV vaccination in India or elsewhere. Experience with the HPV vaccines used in the post-licensure observational study confirms the good safety profile reported in clinical trials. 
As demonstrated in extensive clinical trials and through post-marketing surveillance, HPV vaccines continue to show high safety profiles with very low rates of serious side effects and no causal links to any reported deaths. In its 2009 position paper on HPV vaccination, the World Health Organization stated that “WHO’s Global Advisory Committee on Vaccine Safety (GACVS) concluded that both vaccines had good safety profiles.” The GACVS clearly stated in its review that “No concerns with the safety profile were identified.”

In the large cohorts of girls vaccinated in Andhra Pradesh and Gujarat, six deaths were reported in the weeks or months following HPV vaccination. None of these deaths was causally associated with the vaccine.

In an article from the April 9, 2010, edition of the Times of India, Dr. V.M. Katoch, director general of the Indian Council of Medical Research, stated that the four deaths in Andhra Pradesh were not due to the vaccine. He explained that, “two deaths were due to poisoning, one died of drowning, and another due to pyrexia of unknown origin.” The article went on to cite official reports from the relevant district officials that confirm that the deaths were not due to HPV vaccination. The two deaths in Gujarat were attributed to malaria and snake bite.

Serious side effects of HPV vaccination are very rare. Very few serious side effects have occurred in the post-licensure observational study. 
The WHO position paper on HPV vaccines states that, “in clinical trials, mild and transient local reactions at the site of injection (erythema, pain, or swelling) were 10–20% more frequent among those who received the current HPV vaccines than in their respective control groups, but no systemic adverse reactions assessed to be causally associated with the HPV immunization have been reported.”

And the US Centers for Disease Control and Prevention state, “As of May 1, 2009, more than 24 million doses of Gardasil were distributed in the United States…Experts have not found a common medical pattern to the reports of serious adverse events…that would suggest that they were caused by the vaccine.”

Of the more than 23,000 girls vaccinated in India, three were hospitalized after vaccination as a cautionary measure. All three were released soon afterward, following observation.

HPV vaccines protect against the most common causes of cervical cancer.
Of the approximately 15 types of HPV that may cause cancer, two types (HPV 16 and HPV 18) cause more than 70 percent of cervical cancer cases in India and around the world. Both vaccines have demonstrated high efficacy against precancerous lesions caused by these two types of HPV.

Prior clinical trials have shown that efficacy in preventing precancerous lesions caused by HPV 16 or 18 for both vaccines is very high—greater than 92 percent in women who have not been previously infected with these viral types. Furthermore, results from several international, randomized controlled studies with follow up of nearly eight years have shown that both vaccines induce high levels of antibody titers against vaccine-specific HPV types and that the antibody levels were about tenfold higher than those following natural infection with HPV. The antibody levels correlate with vaccine efficacy. Current evidence does not indicate a reduced performance at eight years, nor does it indicate a need for booster doses.

The study population is representative of the population of the two states, including girls living in urban, rural, and tribal areas.
Since the post-licensure observational study seeks to determine vaccine coverage achieved, feasibility, acceptability of HPV vaccination, and implementation costs associated with different vaccination strategies in a variety of socioeconomic settings, blocks (neighborhoods) were selected to represent diverse populations that would be eligible for HPV vaccination through a public health program, including those in urban, rural, and tribal settings.

The role of the vaccine manufacturers is limited to vaccine donations; no funds from manufacturers have been used for this project.
The vaccine manufacturers were not involved in designing the post-licensure observation study protocols, recruiting participants, implementing vaccination, or any other activities beyond donating vaccines.

For more information

Readers interested in seeing the source materials for statements above may contact PATH at info@path.org.

Posted April 22, 2010. Updated April 27, 2010.