Capacity Building Workshop on Ethics and Regulation of Clinical Trials in India,organized by Sama–Resource Group for Women and Health, to be held at Bhopal on December 18-19th, 2013

A similar workshop was conducted at Delhi in February, 2013. Sama has been consistently working on the issues of rights violations and ethical misconduct in clinical trials in India over the last 4 years. In recent past there have been many examples of clinical trials that have taken place that disregarded ethical aspects and participant rights. At the levels of planning, design and implementation, there exists a striking lack of transparency thus jeopardizing the reliability and validity of drug research in the absence of adequate regulatory jurisdiction and systematic review of the industry. Recent parliamentary a standing committee reports on the functioning of the CDSCO office and on the clinical trials conducted by PATH validate the concerns raised by civil society groups. Subsequent developments in the regulatory framework for the clinical trials make it even more appropriate to discuss the issues regarding clinical trials. In this context, we are organizing this capacity building workshop to inform and initiate dialogue with regard to existing regulatory and provisions regarding clinical trials.

 

Trial and Error: Ethical Violations of HPV Vaccination Trials in India

On July 9, 2009, the Andhra Pradesh Minister for Health and Family Welfare in association with the Indian Council of Medical Research (ICMR) and PATH (Programme for Appropriate Technology in Health) International a non-profit organization based in USA launched what it described as a ‘demonstration project’ for vaccination against cervical cancer. The vaccine, against the Human Papillomavirus (HPV), which is one of the most common families of viruses and the source of a common sexually transmitted infection, was administered to 14,000 girls between the ages of 10 and 14 in three mandals – Bhadrachalam, Kothagudem and Thirumalayapalem – of Khammam district in Andhra Pradesh. In Andhra Pradesh, the vaccine used was Gardasil, manufactured by Merck Sharpe and Dohme, the Indian subsidiary of Merck and Co. Inc., a US-based pharmaceutical company.

In a similar project, on August 13, 2009, the Gujarat government launched a two-year ‘Demonstration Project for Cancer of the Cervix Vaccine’ in three blocks of Vadodara District – Dabhoi, Kawant and Shinor – to administer three doses of the HPV vaccine to 16,000 girls between 10 and 14 years. There were reports of deaths of four girls from Andhra Pradesh and two girls from Gujarat following the administration of the vaccine.

During March 27-30, 2010, a team of women’s and health activists visited Bhadrachalam mandal, one of the three mandals of Khammam district where the ‘demonstration project’ was undertaken to understand the ground reality; in particular, to look at the nature and procedures of taking consent and providing information to the girls and their parents, and the availability of the health infrastructure required to support cancer screening and prevention.

The children selected to participate in this project were from four social groups with poor economic background – scheduled tribes, scheduled castes, Muslims and other backward communities. Majority were tribal children, whose parents were agricultural labourers. Some girls were from families that have been displaced by the ongoing conflict in the neighbouring state of Chhattisgarh; circumstances that serve only to compound their vulnerability.

Majority of the vaccinated girls in Bhadrachalam were residents of ashram paathshalas (boarding schools). The selection of these girls for the project is striking, given that their parents, living separately, cannot monitor and respond to any adverse developments in their children’s health. Moreover, this has allowed providers to conveniently side-step the provision of parental consent.

The vaccine was administered through a camp approach in the hostels and school campuses. In many instances, the wardens of the residential schools and hostels were asked to provide consent or permission for vaccination, while parents were not informed. The very nature of this project appears to be in violation of all ethical norms as a warden, whether a legal guardian or not, be allowed to provide consent for hundreds of children without consulting their parents, who are their natural guardians;

The ‘consent form’ was used primarily in the case of non-residential schools, and children were asked to get signatures from their parents. This violates the designated protocol for obtaining informed consent, whereby the ‘researcher’ is required to directly provide information mandatory for consent to the person(s), in this case the parents.

Selected girls were given HPV Immunization Cards, which were in English – a language that neither the girls, nor their parents, were familiar with. Further, all involved (the wardens, teachers and students) believed the project to be part of the public immunization program, and had no idea that they were in fact, part of a research study. They were not even aware that they had a choice regarding participation in the study.

Many stated that they were given to understand that the government was providing free of cost an expensive vaccine that would prevent ‘uterine’ or ‘cervical cancer’. This would otherwise be unaffordable for them. Several parents brought their daughters to the vaccination camps themselves when they heard about the project. One mother said, “Since it was a vaccine being given by the government, we all trusted it blindly and considered it reliable, like any other vaccine that is given in the immunization programme”. Participants were verbally informed that the vaccine would provide life-long protection, with no side-effects or impact on fertility. The fact that the vaccine protects against only two types of the HPV virus and that regular pap screening is required even after vaccination was mentioned at all- neither verbally, nor in the written material given to some girls. Since the long term efficacy and protection by the vaccine is unknown, it cannot be claimed that even 60-70% protection will be achieved. Currently is also unclear if, when and how booster shots will be required.

Many of the vaccinated girls continue to suffer from stomachaches, headaches, giddiness and exhaustion. There have been reports of early onset of menstruation, heavy bleeding and severe menstrual cramps, extreme mood swings, irritability, and uneasiness following the vaccination. No systematic follow up or monitoring has been carried out by the vaccine providers.

While the project was being carried out under the banner of the National Rural Health Mission (NRHM) shockingly enough the Mission’s mandate does not extend to or mention any such research project. Further, the existing health infrastructure in the region is woefully inadequate. Pap smear facilities are conspicuous by their absence in all government facilities in the area. The entire tribal mandal of Bhadrachalam does not have a single gynaecologist.

The vulnerability of this these communities are thus further compounded by of the lack of access to health care, lack of access to information and absence of mechanisms for reporting adverse effects.

The state government has claimed that the deaths of the four girls post-vaccination were unrelated to the ‘project’. However, parents of Kudumula Sarita, who died in January 2010, believe that their daughter died due to the vaccination, and not by consuming pesticide, as has been officially declared by the authorities.

The trial has been suspended temporarily by the government after a strong campaign by health networks, women’s groups and by parliamentarians. A committee has been set up by the government to conduct an inquiry, the composition of the committee leaves much to be desired and is far from representative.

The Ministry of Health and Family Welfare, on 22^nd April 2010, finally conceded that the HPV vaccination project was in fact, a “post-licensure operational research study”, which on further clarification, was confirmed to be a Phase IV, post marketing, clinical trial.

On 29^th April, the ICMR admitted that their ethical guidelines had been flouted in the course of this trial.

Press Conference on HPV Vaccines

On the occasion of World Health Day, Jan Swasthya Abhiyaan (JSA), All India Democratic Women’s Association (AIDWA), Sama – Resource Group for Women and Health and Saheli Women’s Resource Centre organised a Press Conference to highlight our concerns regarding the HPV vaccines and to voice our opposition to the unethical nature of the ongoing HPV vaccination ‘projects’ being conducted in Andhra Pradesh and Gujarat by PATH International, in collaboration with ICMR and the State Governments.

The safety and the efficacy of the two HPV vaccines Gardasil and Cervarix is highly suspect and a number of very serious side effects, including deaths have been observed across the world, in vaccinated girls.

As per the extensive documentation by a fact finding carried out by local groups in Khammam district in Andhra Pradesh (where 14000 girls in the age group if 10 – 14 years have been vaccinated with the three doses of HPV vaccine), the adverse reactions faced by over 120 girls include epileptic seizures, severe stomach aches, headaches and mood disorders. The matter has further gained grave urgency with the deaths of four girls in the area. Moreover, the very basis of the project is in direct violation of both, the Governments own Ethical Guidelines of Research on Human Subjects and the rights of children as secured by national law as well as international conventions that India is a signatory to.

Other serious issues include the unethical licensing of the two vaccines for marketing as so-called preventives against cervical cancer, and the aggressive promotion by the manufacturers in schools, residential localities and so on through pediatricians and gynaecologists.

The key findings from a fact-finding visit to Khammam district in Andhra Pradesh were also shared at the conference.

The speakers at the conference included:

Brinda Karat – Member of Parliament

Amit Sen Gupta – Jan Swasthya Abhiyaan

Sarojini N. –  Sama Resource Group for Women and Health

Kalpana Mehta –  Saheli Women’s Resource Centre

Sudha Sundararaman – All India Democratic Women’s Association

Venue: Indian Women’s Press Corps (IWPC), 5 Windsor Place, Ashoka Road, New Delhi
Date:  April 7^th, 2010
Time: 1:30 – 3:30 pm

Visit http://www.hindu.com/2010/04/08/stories/2010040857390100.htm and http://www.dnaindia.com/india/report_cancer-vaccine-programme-suspended-after-4-girls-die_1368681 to view some of the news coverage.

Press Release

April 7^th, 2010 – World Health Day

Unethical Medical Intervention to prevent HPV infection by the government in collusion with drug company and foreign NGO renders poor tribal girls dead and debilitated

Protests, representations and extensive coverage in the media against PATH-ICMR project being carried out in AP and Gujarat seem to have fallen on deaf ears and the government has gone ahead with a vaccination programme with Gardasil (HPV vaccine manufactured by Merck) leading to four deaths and 120 girls suffering from debilitating new illnesses like epilepsy, headaches, stomach disorders and early menarche.

The girls, 10-14 years old, belonging to poor families, were enrolled in a study being carried out jointly by PATH (an International NGO), Indian Council of Medical Research and the respective state governments funded by Bill and Melinda Gates Foundation. The objective of this two year study is to look into acceptability and service delivery issues of Gardasil, marketed in India by MSD Pharmaceuticals Pvt. Ltd, being misleadingly promoted as a preventive for cervical cancer.

The literature circulated in the project makes outright false statements about its safety, efficacy and duration of effectiveness. The girls and their parents have been told through the project documents that the vaccine will give life long immunity, has no side effects other than minor ones like fever and rash and will not affect future fertility of the young girls.

When deaths started getting reported local groups in Andhra Pradesh were alarmed by and carried out a fact finding to discover that no consent was taken from parents and the girls and their families have been left uncared for. Post mortem reports were also not easily accessible, and in cases of death cover up was the general dictum.

We question:

1. Why are poor girls and their families being actively misled? Who is liable for the debilitating effects of the vaccine and who will medically look after these girls and pay compensation for the damages suffered by these people?
2. How has the government embarked on this study of giving three injections to the girls when it is also planning a massive multi-centric dose determination study to see if two doses will suffice?
3. How has the Drugs Controller General granted approval to the vaccine without proper research in India? For a drug to be administered to children, it has to go through stages of clinical trial, including Phase 3 adult clinical trials. So far with Gardasil only one trial has been carried out with just a small sample of 110 girls which has followed them up for just one month after the completion of vaccination and that too only to look at the immune response post vaccination. The vaccine has also been approved for adult women till 27 years of age without doing any trials with them at all.
4. Why are these studies being carried out when at various times the concerned government officials have gone on record to say that it is not feasible for the vaccine to be introduced in the Indian Public Health system given its costs? Is it not then using these poor girls as guinea pigs for a vaccine which can be used only in the private market by well to do families? Why is a two year study being carried out with no future guarantee even for the subjects of this study to keep them protected with boosters when they actually get married by when the effect of this vaccination will wear off? The effect of the vaccine seems to wear off after 4-5 years, and will require periodic booster injections to retain claimed effectiveness.

The path of licensing of the vaccine in India raises many serious questions as time and again scientific logic and the ethical guidelines have been violated at each step. Our law clearly states that no trials of drugs can be conducted among children before trials are conducted on adults. While the other HPV vaccine, Cervarix, made by GlaxoSmithKline has also been licensed in India it has been approved for use for children without any trials among them at all. It should be remembered that last year the two drug companies had engaged in massive advertisement of these vaccines in the media and are continuing with giving incentives to doctors and holding promotional camps in schools among the paying segment of the market.

All this is being done for products which have no proven value. Even the license given by US FDA has asked Merck to actually study whether there is a reduction in the incidence of cervical cancer due to vaccination.

Even as their effectiveness and usefulness remains unproven information on the adverse effects of these vaccines are pouring in from all quarters. The tally in US alone crossed the mark of 17000 adverse effects (as reported under the voluntary adverse effects reporting system); and even the US FDA gave a hearing to health advocates to present the case against the vaccines on March 12, 2010. The adverse effects include heart, immune, blood clotting, respiratory, nervous, digestive and musculoskeletal systems and occur with far greater frequency than those observed with any other vaccines. Many experts and established medical journals have already termed it the biggest public health experiment.

In the public health system of India this vaccination will prove to be an expensive and hazardous exercise. These vaccines at best protect against two sub types among 15 which are associated with cervical cancer and hence ideally women will have to undergo pap smear tests for an effective cancer control strategy along with various hygiene and nutrition related strategies. Unfortunately, there is no investment in screening which can help the adult population today.

We demand:

1. Complete suspension of all studies and trials with Gardasil and Cervarix and suspension of their licence for marketing in India till such time that a public enquiry is held on their licensing in violation to the India law.

1. Proper enquiry in the deaths in Khammam that have been dubbed as suicides. Unless it becomes clear that the vaccine has no impact on the mental health of girls the project authorities cannot be absolved of the blame.
2. Each vaccinated girl be examined by independent authority to assess the range and incidence of side effects. While this will provide the much needed information about vaccine safety it will also detail the care that these girls require and the compensation they and their families deserve for having been actively misled.

4. Proper long term follow up of the vaccinated girls till they get married and have children and booster doses at the right time free of cost, with full informed consent for those girls who wish to continue vaccine protection.

Unless the government details a plan for cervical cancer control, with full compliment of boosters, screening and treatment this project is sheer experimentation with innocent, vulnerable and poor people of the society who can not afford this expensive vaccine. According to us the government is constitutionally bound to take care of the life of all citizens and not subject them to new medical problems at the behest of foreign NGOs.

Sama                      All India Democratic Women’s Association                   Saheli

All India People’s Science Network                  Jan Swasthya Abhiyan

Memorandum to the Health Minister on World Health Day Opposing HPV Vaccinations

7th April 2010: World Health Day

To,

Shri Ghulam Nabi Azad,
Union Minister for Health and Family Welfare,
Ministry of Health and Family Welfare,
Nirman Bhavan,

Maulana Azad Road,
New Delhi 110 011

Date: April 7^th, 2010
Subject: Opposition against the unethical nature of the ‘demonstration project’ for the Human Papilloma Virus (HPV) vaccine being conducted in Andhra Pradesh and Gujarat.

Sir,

We the undersigned public health organizations, health networks, medical professionals, human rights groups and women’s groups write to voice our intense opposition to the unethical nature of the ongoing HPV vaccination ‘projects’ being conducted in Andhra Pradesh and Gujarat by PATH International, in collaboration with ICMR and the State Governments. We also strongly stand in solidarity with the local efforts initiated by groups and Networks in Andhra Pradesh following the death of 4 young, tribal girls in Khammam district following the vaccination.

As was clearly detailed in a Memorandum, dated October 1^st, 2009, signed by over 50 groups and individuals, the efficacy of the vaccines Gardasil and Cervarix is highly suspect and a number of very serious side effects, including deaths have been observed across the world, in vaccinated girls. As per the extensive documentation by a fact finding carried out by local groups in Khammam district in Andhra Pradesh (where 14000 girls in the age group if 10 – 14 years have been vaccinated with the three doses of HPV vaccine), the adverse reactions faced by over 120 girls include epileptic seizures, severe stomach ache head aches and mood swings. There have also been reports of early onset of menstruation following the vaccination, heavy bleeding and severe menstrual cramps. Moreover, the current, ‘demonstration project’ has no follow up mechanism in place for girls who suffer from adverse events following the vaccination. As a result many of the girls have had to seek treatment in the private sector and with local quacks.

The matter has further gained grave urgency with the deaths of four tribal girls in the area. The local authorities have refused to take cognizance of their probably association with the vaccine, two of the deaths have shockingly been written off as suicides, when the evidence clearly suggests otherwise! Along with sounding extremely suspicious this has also raised valid concerns of this being a massive cover up exercise.

Above all, the very nature of this project seems to be unethical and violates all norms of conducting trials on human subjects. In many Aashram Schools, a verbal consent to vaccinate girls living in the Aashram schools has been taken from the Hostel Warden/ teacher in-charge, while parents were not even informed about it. In cases of day scholars, where consent was obtained from the parents, the form given held the nomenclature of an approval form “Angikaara Patram” and only provided minimal information with no provisions for addressing in detail the need for follow. In fact, when a lady warden of a hostel objected when she was told that the vaccine was being administered on girls in the hostel, she was informed that this vaccine is mandatory! This is a travesty of the entire concept of “informed consent.”

Consent and information, reserved for only a few, is a farce and was based on provision of wrong information. Many of the girls were told that the vaccine would prevent uterine cancer and would provide life-long protection. This information is factually incorrect and provides the recipient with a false sense of security against the “dreaded” disease. As per the claims by the pharmaceutical companies themselves, the vaccine only protects against infections caused by 2 types of HPV virus (of the 13 high risk strains of HPV) that are associated with a higher risk of cancer of the cervix. Moreover, once again as claimed by the companies themselves, the protection by the vaccines is understood to last for only 4.5 years with Gardasil and 7 years with Cervarix, while, the need for a booster has not yet been established. There are reports in developed countries that this number too is an over estimation and the protection in fact may not last for more than 3-5 years.

It is also shocking and worrying that these projects are being carried out under the NRHM banner, while the existing medical facilities in the region are extremely inadequate. While Pap smear facilities are not available in Government facilities in the area (a must for even those who have been vaccinated against HPV) the absence of a Gynaecologist in the entire tribal mandal of Bhadrachalam is absolutely appalling. It is highly irresponsible and negligent of the State and Central government that such large scale exploitation of poor and tribal populations is being carried out by subjecting them to a vaccine with a dubious track record, when even the basic public health facilities are not in place.

Although, the nomenclature suggests otherwise, the secrecy regarding the non-transparent selection criteria of the area, the girls and the aim of the project has raised undeniable fears that this is a Phase IV clinical trial being carried out under the guise of a ‘demonstration project’ Moreover, there is an inexcusable lack of clarity with regards to the role and accountability of international agencies such as PATH and Bill and Melinda Gates Foundation that appear to be funding this project. It is beyond doubt the worst case of human rights violation, where young healthy girls have to die for being part of a state-endorsed experiment, initiated by a profit making private company.

This constitutes shocking criminal negligence on the part of the authorities, who have provided permission and support to this programme within the public health system. We need immediate government intervention to prevent this. No NGO should be given such permission for clinical trials/ demonstration projects, regardless of which vaccine or drug is being administered. Financial support from the industry or from an international organization should not be the criteria to introduce any vaccine, whether in a pilot project or in the universal immunization programme.

Thus, standing in solidarity with groups, parents and the girls in Andhra Pradesh, we demand that:

1. the government should make sure that all these projects are immediately brought to a halt across the country, till concerns relating to safety, efficacy and cost effectiveness of the planned interventions are reevaluated.
2. the government should set up an  inquiry:
   1. into the deaths of the tribal girls;
   2. into the side effects of the vaccine on affected girls, so that responsibility can be fixed and action taken.
3. All agencies involved in the project need to be held accountable and culpable for any ethical, legal, medical violations that emerges in such an enquiry
4. the State Government should take immediate action, including providing compensation to the families who have lost their children and to the children suffering side-effects
5. all the sufferers should be provided proper medical treatment and follow up
6. the Government place in public domain::

• All the documents pertaining to the agreement with vaccine manufacturers and all other bodies regarding the government’s plan to introduce the HPV vaccine.
• The list of projects planned, proposed, approved and completed, agencies involved, donors involved and proposed locations. and all the results of the pilot phase and  clinical trials

7.  the Government institute a national policy on this kind of medical ‘experimentation’, and  a pro-people vaccine policy based on public health needs

Signed by

1. Jan Swasthya Abhiyan (JSA)

2. All India Democratic Women’s Association (AIDWA)

3. All India Drug Action Network (AIDAN)

4. All India Peoples’ Science Network (AIPSN)

5.  Federation of Medical and Sales Representatives’ Associations of India (FMRAI)

6. Sama- Resource Group for Women and Health, Delhi

7. Action India, Delhi

8. HAQ- Centre for Child Rights, Delhi

9. KRITI, Delhi

10. Jagori, Delhi

11. Breastfeeding Promotion Network of India, Delhi

12. Centre for Women’s Development Studies (CWDS), Delhi

13. Centre for Legislative Research and Advocacy (CLRA), Delhi

14. Delhi Forum, Delhi

15. Diverse Women for Diversity, Delhi

16. RAHI Foundation, Delhi

17. SANGRAM, Maharashtra

18. Adivasi Aikya Vedika, Andhra Pradesh

19. Anthra, Hyderabad, Andhra Pradesh

20. Yakshi, Hyderabad, Andhra Pradesh

21. Asmita Collective, Secunderabad, Andhra Pradesh

22. Adarsha Women’s Society, Khammam, Andhra Pradesh

23. Koyitur Kutuva, Khammam, Andhra Pradesh

24. Adivasi Seva Samiti, Khammam, Andhra Pradesh

25. ANKURAM, Hyderabad, Andhra Pradesh

26. Girijana Deepika, East Godavari, Andhra Pradesh

27. Tholakari Adivasi Mahila Vedika, East Godavari, Andhra Pradesh

28. Adiavsi Seva Sangham, West Godavari, Andhra Pradesh

29. Arunodaya Grameen Abhivridhi Sangham, Vijayanagarm, Andhra Pradesh

30. Adivasi Chaitanya Sangham, Adilabad, Andhra Pradesh

31. Chinnayya Adivasi Vikasa Sangham, Srikakulam, Andhra Pradesh

32. Manyam Girijana Seva Sangham, Vijayangaram, Andhra Pradesh

33. Adivasi Ahara Bhadrata Sangham, Visakhapatnam, Andhra Pradesh

34. Jeevam, Visakhapatnam,  Andhra Pradesh

35. Savara mahila sangham, Srikakulam, Andhra Pradesh

36. Agricultural and Social Development society (ASDS), Khammam, Andhra Pradesh

37. Natwan Sangham (Tribal Women Federation), Khammam, Andhra Pradesh

38. Rukmini Rao, Gramya Resource Centre for Women, Hyderabad, Andhra Pradesh

39. Usha Seethalakshmi, Freelance Researcher & Consultant, Hyderabad, Andhra Pradesh

40. Kalpana.Kannabiran, Hyderabad, Andhra Pradesh

41. Vasanth Kannabiran, Hyderabad, Andhra Pradesh

42. Lalitha Kumari, Hyderabad, Andhra Pradesh

43. BHUMIKA Magazine, Andhra Pradesh

44. Anchita Ghatak, Parichiti- A Society for Empowerment of Women, West Bengal

45. Anu Gupta, Eklavya, Madhya Pradesh

46. Bimla Chandrasekar, EKTA, Tamil Nadu

47. Dr Veena Shatrugna, Hyderabad, Andhra Pradesh

48. Chinu Srinivasan, SAHAJ, Baroda, Gujarat

49. Dr Gopal Dabade, Drug Action Forum, Karnataka

50. Jaya Velankar, Women’s Rights Activist, Delhi

51. Dr. Kaveri Rajaraman

52. K R Nayar, Jawaharlal Nehru University, Delhi

53. Manisha Gupte, MASUM, Pune, Maharashtra

54. Dr Mira Shiva, Initiative for Health Equity and Society (IHES), Delhi

55. Dr Mohan Rao, Jawaharlal Nehru University, Delhi

56. Neha Madhiwala, Centre for Studies in Ethics and Rights (CSER), Mumbai, Maharashtra

57. Prof Padmini Swaminathan, Madras Institute of Development Studies, Chennai, Tamil Nadu

58. Pallavi Sobti-Rajpal, Utthan, Gujarat

59. Rajashri Dasgupta, Kolkata, West Bengal

60. Renu Khanna, Sahaj, Baroda, Gujarat

61. Dr Vandana Prasad, Delhi

62. Ranjan De, Filmmaker, Delhi

63. Dr. Ajay Kumar Khare, Madhya Pradesh Vigyan Sabha/JSA, Bhopal, Madhya Pradesh

64. Bishakha Dutta, Filmmaker, Mumbai, Maharashtra

65. Dr. Y. Madhavi, Scientist, Council of Scientific and Industrial Research (CSIR), Delhi

66. Saheli, Delhi

67. Salai Selvam, Tamil Nadu

68. CREA, Delhi