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Table 3 Derived questions based on a content analysis of the media coverage for HPV vaccines worldwide from 7 September to 22 October 2015 and categorised by themes

From: Application of real-time global media monitoring and ‘derived questions’ for enhancing communication by regulatory bodies: the case of human papillomavirus vaccines

Categories: themes and high-level questions Sub-categories: additional aspect-specific questions
Theme 1 - Assessment scope: 1.0. What is the scope of the assessment conducted for the EU referral procedure for HPV vaccines? 1.1. Why does the procedure focus on CRPS and POTS as defined by complex and difficult-to-apply/ascertain case definitions?
1.2. Why have concerns over autoimmune diseases with HPV vaccines been excluded from the assessment?
1.3. Why does the evaluation not cover the entire benefit-risk balance of HPV vaccines?
Theme 2 - CRPS and POTS case data: 2.0. What kind of case reports of CRPS and POTS in association with HPV vaccines have been reviewed by the authorities, and how? 2.1. How many case reports of CRPS and POTS in association with HPV vaccines have been received by the authorities, who reported the cases to the authorities and who are the primary reporters?
2.2. Who confirmed the cases as CRPS and POTS cases?
2.3. How many cases have been received with symptoms of, or similar to those of, CRPS and POTS but have not met the criteria of the case definitions, how were these cases reviewed/followed up and how did they have an impact on the assessment outcome?
2.4. Have all reported cases been followed up by the authorities in order to obtain more information (to allow for causality assessment)?
2.5. What is the outcome of the analysis of data recorded in EudraVigilance (the adverse reaction database of the EU regulatory network) requested by parents who have participated in the EMA meeting with concerned vaccinees and parents to present their concerns and experiences?
2.6. How were the cases reviewed that had been submitted to the authorities by the parents’ groups as invited by the EMA?
Theme 3 - Frequency assessment: 3.0. What are the reporting rates and actual frequencies of CRPS and POTS in association with HPV vaccines? 3.1. How are these frequencies calculated?
3.2. Where have background frequency data been obtained from, and how confident can one be in their accuracy?
3.3. What is the likely magnitude of underreporting, and has a sensitivity analysis been performed for the observed/expected analysis to take underreporting into account?
3.4. Why are the reporting rates for (any) adverse reactions higher for HPV vaccinesthan for other vaccines?
Theme 4 - Other (i.e. not case) CRPS and POTS data: 4.0. What kind of data has been reviewed for the EU referral procedure for HPV vaccines in addition to individual case reports? 4.1. What is the nature of these data, and who provided them?
Theme 5 - Assessment of causal association: 5.0. How has the assessment of CRPS and POTS in possible causal association with HPV vaccines been performed? 5.1. Have all potential aetiological pathways been investigated, e.g. autoimmune pathway and impact of female hormones on susceptibility for autoimmune disease?
5.2. How has causal association been ruled out?
Theme 6 - Overall safety and other safety concerns: 6.0. What are the overall safety database and safety study results for HPV vaccines? 6.1. What was the knowledge base at the time of granting the marketing authorisation, and were the vaccines sufficiently tested at the time?
6.2. How are data assessed for autoimmune diseases, including multiple sclerosis and Guillain-Barré syndrome?
6.3. How are data assessed for infertility, miscarriage and stillbirth?
Theme 7 - Aluminium: 7.0. What is the knowledge about the safety of aluminium/AS04 as adjuvant? 7.1. What are the plasma levels for aluminium after vaccination with current HPV vaccines and with the future Gardasil-9® compared to typical food intake?
7.2. How does the clearance process of aluminium in the human body work?
7.3. Since when has the rate of autism diagnosis been increasing, and is there a temporal association with the use of aluminium in vaccines?
7.4. What is known about a link between AS04 (aluminium hydroxide + monophosphoryl lipid A) and autism?
7.5. How similar is AS04 to AS03 (squalene + dl-α-tocopherol + polysorbate 80), which is the adjuvant in Pandemrix® for which cases of narcolepsy were reported as suspected adverse reactions?
Theme 8 - Data trustworthiness: 8.0. Are the data for the EU referral procedure for HPV vaccines trustworthy? 8.1. What safeguards are there to ensure that marketing authorisation holders do not manipulate data they submit to the authorities?
8.2. Have data been solicited by the authorities from independent sources?
Theme 9 - Assessment standards and integrity: 9.0. How can it be demonstrated that signal detection, risk evaluation and decision-making have been performed to highest standards during the EU referral procedure for HPV vaccines? 9.1. Have the authorities taken seriously the vaccinated females experiencing CRPS and POTS?
9.2. How do the authorities manage their conflict of interests?
9.3. Why was the signal of CRPS and POTS with HPV vaccines not identified earlier, and why was the referral procedure only initiated at the request of Denmark and not earlier by the EMA?
9.4. Why did the EMA not apply the precautionary principle and suspend the vaccine while investigations were ongoing?
Theme 10 - Benefit: 10.0. What is the knowledge on the benefit and effectiveness of HPV vaccines? 10.1. How does the vaccine intervene protectively in the pathway of cancer development?
10.2. How long is the vaccination effective in vaccinees, and what should vaccinees do after immunity has decreased?
10.3. What is the potential of strain replacement, and how will this have an impact on cancer rates?
Theme 11 - Benefit-risk balance: 11.0. What does the statement ‘the benefits outweigh the risks’ mean? 11.1. Is this statement only applicable at population level or also at the individual level, and does a positive benefit-risk balance apply to all potential vaccinees or are there individuals to whom the statement does not apply?
11.2. How are healthcare professionals provided with information so that they can communicate well with potential vaccinees and parents about the individual benefit-risk balance?
Theme 12 - Further steps and research: 12.0. What will the impact of the EU referral outcome be, and will further research be done? 12.1. How do vaccine evaluations by the authorities have an impact on immunisation policies?
12.2. What kind of further research will be done, and what will be the study objectives?
12.3. How will independence of this research be ensured?