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Undeniable Violations and Unidentifiable Violators

The Human Papillomavirus vaccine "demonstration projects" conducted by a United States non-governmental organisation in collaboration with the Indian Council of Medical Research were suspended by the central government in 2010, following the deaths of seven tribal girls and pressure from civil society groups. An enquiry committee constituted to look into the "alleged irregularities" in the conduct of these projects has given its final report. Despite evidence of clear violations, however, the committee has absolved all involved in the project of responsibility.

COMMENTARY

Undeniable Violations and Unidentifiable Violators

Sarojini N, Anjali Shenoi, S Srinivasan, Amar Jesani

The Human Papillomavirus vaccine “demonstration projects” conducted by a United States non-governmental organisation in collaboration with the Indian Council of Medical Research were suspended by the central government in 2010, following the deaths of seven tribal girls and pressure from civil society groups. An enquiry committee constituted to look into the “alleged irregularities” in the conduct of these projects has given its final report. Despite evidence of clear violations, however, the committee has absolved all involved in the project of responsibility.

Sarojini N (sarojinipr@gmail.com) is with the Jan Swasthya Abhiya and Sama-Resource Group for Women and Health, Anjali Shenoi (sama.womenshealth@gmail.com) is with the Sama-Resource Group for Women and Health, S Srinivasan (sahajbrc@gmail.com) is with LOCOST, Vadodara, and the All India Drug Action Network and Medico Friend Circle, Amar Jesani (amar.jesani@gmail.com) is on the editorial board of the Indian Journal of Medical Ethics.

T
he Human Papillomavirus (HPV) vaccine “demonstration projects” conducted by an American nongovernmental organisation (NGO) PATH, in collaboration with the Indian Council of Medical Research (ICMR) and the state governments of Andhra Pradesh (AP) and Gujarat, have raised several pressing questions related to the ethics of biomedical research in India (Sarojini et al 2010).

The HPV vaccine “demonstration projects” were suspended by the ministry of health and family welfare in April 2010 following concerns raised by Communist Party of India (Marxist) MP Brinda Karat, public health groups, women’s groups, and child rights groups. Pressure from the civil society groups and others followed reports of the deaths of six girls (four in AP and two in Gujarat) and other ethical violations. (The seventh death has come to light in the committee’s report.) The ministry appointed a committee to enquire into the “alleged irregularities in the conduct of studies using HPV vaccine by PATH in India”. It included S S Agarwal, former director, Sanjay Gandhi Postgraduate Institute of Medical Sciences; S P Agarwal, former director general of health services and Suneeta Mittal, Head of obstetrics and gynaecology department, All India Institute of Medical Sciences (AIIMS). The committee was also assisted by three expert members (Rani Kumar, Dean, AIIMS; A K Dutta, Head of Paediatrics, Kalawati Saran Hospital and Y K Gupta, Head of Pharmacology, AIIMS) to look into various aspects of the projects including the linkages of the deaths with the vaccine, and the ethics of project implementation.1

While identifying several deficiencies in the planning and implementation of the project, the committee’s final report has failed to hold those involved in the projects such as PATH, ICMR, the state governments of AP and Gujarat, and the ethics committees accountable. This is both disappointing and alarming. Some of the main issues include:

1 Nature of the Projects

PATH and ICMR have reiterated several times that the demonstration projects do not classify as clinical trials since they did not seek to evaluate the efficacy and safety of the vaccine, no biomedical outcomes were being researched, no blood or other samples were drawn, and no therapies were tested (PATH 2010). However, as Gupta observes in the committee’s report, the nature and objectives of these projects make it evident that they are in fact clinical trials, wherein the projects were a “study of a pharmaceutical product carried out in human participants” and “4 of 5 primary outcome measures proposed in the study related to evaluation of the safety of the vaccine in population setting. The very principles used to define a clinical trial by Central Drugs Standard Control Organisation (CDSCO) and Schedule Y (DCA) can be applied to the demonstration projects conducted by PATH.

Moreover, the committee report in Section 7 (p 73) of its findings has explicitly stated that,

It is of the opinion that by whatever name you call it, the project proposal has been carried out as research on human participants. And as such it had to follow all the guidelines and statutory requirements applicable for research on human participants. Monitoring and management of Adverse Events/ Serious Adverse Events (SAE) should have been more vigorously pursued.

2 Selection of Study Area

Gupta in his report to the committee has specifically stated that the study has been carried out on a “vulnerable population”. However, the report once again falls short by stating that while the stratification (urban, rural and tribal) “seems appropriate, caution is required”. The committee in Section 7.5 (p 75) has further stated that,

…. 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 tribal and more difficult areas could have been chosen in the later round. The standard of medical care in remote areas is generally not of the same level as in the urban areas. It would

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have been easier to provide proper medical care at urban district level for any SAE, particularly the life threatening SAE. It would have been better investigated to document the cause of the illness even if unrelated. The adequacy of existing AEFI (adverse events following immunisation) system to measure 4 out of 5 primary endpoints also could have been better tested in the urban area first.

It has also been categorically stressed in Section 8.5 (p 80) that “everyone shall desist from research on tribal population, unless of specific benefit to them”.

3 Process of Obtaining Consent

In her finding, with respect to the process of obtaining informed consent, Rani Kumar explicitly states

…from the numerical analysis it is obvious that the team involved in conduction (sic) of the study on HPV has been very casual in its approach and has ignored many ethical issues such as signatures of parent/guardian, witness, PI (principal investigator) and discrepancy in the date of receiving the vaccine and date of signature (p 49).

Similarly, the committee in its findings in Section 7.1 (p 70) has also declared, “the most significant deficiency in the implementation of the project was the obtaining of consent”. Similarly, the committee in Section 7.14 (p 72) also states that there are ambivalent sentences in the consent form, which can amount to “covert inducement and indirect coercion”, especially in the light of the high cost of the vaccine (Rs 3,000 per dose for three doses).

In AP, the most shocking violation was the Integrated Tribal Development Authority’s orders to hostel wardens, headmasters and teachers to comply with the demands of the project, and “facilitate” the consent taking processes, particularly in the ashram paathshalas (p 51). Approximately 2,763 consent forms out of 14,253 were signed by the hostel wardens/head master in AP. The committee, in Section

7.1.1 (p 70) also mentions that,

…this authorisation runs contrary to the basic principles of obtaining consent as students cannot be considered to have full autonomy in front of their teachers/head master. There is no express approval of the Institutional Ethics Committees (IECs) of MNJIO&RCC (MNJ Institute of Oncology & Regional Cancer Centre), Hyderabad for this provision, nor is there any mention of it in the consent document.

4 Reporting of Adverse Events

The adverse event reporting system has been yet another issue of concern. The committee findings in Section 7.2 (p 74) of the report state,

There has been direct contact with the human participants, they have administered an intervention which is not part of a prescribed prevention, and have expected adverse events. The committee is of the view that in all investigational studies (irrespective of being done with non-licensed or licensed products), particularly those that deal with 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 responsibility of the investigator. Adequate insurance cover for participants to include unforeseen/unexpected or even probable morbidity and mortality events should be a part and parcel of such studies. In this context rule 122-e of the Drugs and Cosmetics Rules, 1945 provides that all vaccines shall be new drugs unless certified otherwise by the licensing authorities under Rule 21, and a new drug shall continue to be considered a new drug for the period of 4 years from the date of its first approval or inclusion in the Indian Pharmacopoeia, whichever is earlier.

Moreover Dutta in his observations has mentioned several unacceptable and prolonged delays in the reporting of adverse events and deaths due to the lack of any independent monitoring systems. Although his observations state that a link between the deaths of seven girls and the vaccine is unlikely, in at least three of these cases no conclusive evidence in this regard could be found. Further, it is shocking that the study protocols did not include a separate component for the surveillance of adverse events, and relied solely on the existing state-run guidelines for the reporting of AEFI. The lack of action taken by the Drugs Controller General of India and the ICMR in the light of delays is also objectionable.

The committee has quite forcefully condemned this laxity and made sound recommendations (p 81)

…besides issuing directions, an active programme needs to be evolved for training investigators and sensitisation of regulatory agencies to specially look for these aspects in any study involving human subjects. There is also need for specific and separate legislation covering all aspects of biomedical and health research involving human participants

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which should provide statutory status to ICMR ethical guidelines and harmonise separate provisions under GCP (good clinical practices) guidelines and Schedule Y of the Drugs and Cosmetics Act.

Further, important questions regarding the follow-up on the girls who have dropped out of the study have not been raised.

5 Lack of Clarity in Finances

The committee has raised certain pertinent questions regarding the financial contributions of the different parties involved. In Section 7.5 of the report (p 75) the committee states,

On the basis of market price of Rs 3,000 per dose the approximate cost of vaccinating 25,000 girls would be aproximately Rs 250 million. What was the financial investment of ICMR and state governments in the project is not provided. The State clearly provided the cold chain and manpower for immunisation. But would it have done so if the vaccine was not free. There is concern about the hidden possibility of a hidden agenda to push this prohibitively expensive vaccine into the Indian Healthcare System. It might have been more prudent if the National Technical Advisory Group on Immunisation (NTAGI) has deliberated on the study prior to its implementation and given its recommendations. The Ethics Committees should have looked into this aspect as well before approving the studies and a speaking mention should have been made in their approval.

6 Need for Insurance Cover

While noting that PATH had taken an insurance cover for itself, the committee states “since the HPV vaccine is a newly developed vaccine, even though licensed, there should have been a provision of insurance coverage for study participants. The need for an Insurance cover is even more since the vaccine is administered to normal healthy individuals that too adolescent girls.”

7 Public Private Partnerships

Though the committee through its report has highlighted the “blurring of the distinction between the National Immunisation Programme, as routine service activity versus the research nature of the HPV vaccination project” they have merely advised “caution” for such partnerships in the future.

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COMMENTARY

Despite the appointed experts pointing out clear violations, the Responsibility section of the report is the weakest with the committee exonerating all involved in the project. This is unacceptable.

8 Accountability

In the light of the committee’s findings immediate action must be taken against ICMR officials, and members of all ethics and advisory committees responsible for and associated with these projects. The punitive action must include the DCGI, PATH and AP officials who ordered the implementation of these projects.

All participants in the study must be monitored and followed up for any adverse events, both serious and non-serious, with the immediate provision of any necessary treatment for at least four years, as prescribed by the Drug Control Autho rity for new drugs.

Note

1 All references to the committee’s statements and their report in this comment are referenced

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from the “Final Report of the Committee appointed by the Government of India vide notification no. V.25011/160/2010-HR dated 15 April 2010, to enquire into Alleged irregularities in the conduct of studies using Human Papilloma Virus (HPV) vaccine by PATH in India”, 15 February 2011.

References

PATH (Program for Appropriate Technology in Health) (2010): “Update: PATH’s HPV Vaccination Project in India”, press release 27 April, viewed on 30 July 2010 (http://www.path.org/news/ an100422-hpv-india.php).

Sarojini, N B, Sandhya Srinivasan, Madhavi Y, Srinivasan S and Anjali Shenoi (2010): “The HPV Vaccine: Science, Ethics and Regulation”, Economic & Political Weekly, 45 (48): 27-34.

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