Clinical Vaccine Development PDF

Clinical vaccine development Valentino D’Onofrio, PhD Clinical Research Coordinator CEVAC Overview 1. 2. 3. 4. What is a clinical vaccine trial? Regulation Ethical review board (ERB) Study participants A. B. C. D. Rights and duties Informed consent Liability and insurance Protection of privacy...

Clinical vaccine development Valentino D’Onofrio, PhD Clinical Research Coordinator CEVAC Overview 1. 2. 3. 4. What is a clinical vaccine trial? Regulation Ethical review board (ERB) Study participants A. B. C. D. Rights and duties Informed consent Liability and insurance Protection of privacy and personal data of the participant A. Reporting adverse events post-vaccination and safety monitoring Blood samples: safety and immunogenicity evaluation 5. Study Design 6. Study Procedures B. 7. Vaccines and vaccine management Vaccine Industry • • • Small part of Pharmaceutical industry Remarkable growth due to new innovative vaccines Key principles o o o o o Assessment of disease burden (& cost) and defining target population Medical need and cost-effectiveness (WHO CHOICE (chosing interventions that are cost-effective) Funding vaccine programmes (e.g. GAVI, Gates Foundation, …) Advanced market commitments (AMC) Recent advances and technology discoveries (e.g. novel adjuvants and delivery systems) Vaccine Development • Vaccine development is a complex and lengthy process • Cost estimates of $1 billion • Emphasis shift from immunogenicity and efficacy to safety and economic considerations o If $1 million is invested annually in R&D, approximately 1 new vaccine every 6 to 8 years is expected o Price of 1 dose à Private market or Government? o But old vaccines remain profitable à new birth cohorts & few competitors • High Failure rate: less than 1 in 15 vaccines achieve licensures: o o o o Incomplete understanding biology of protection Lack of animal models Unpredictability of human immune response Unpredictability of combining components Clincial vaccine trial • Research project that evaluates the safety, immunogenicity and/or efficacy of a new vaccine or improved version of an existing vaccine • With the aim of answering the following question(s): o o o o o o Is the vaccine safe? Which adverse events does it cause, and are these acceptable? Is the vaccine efficacious? Which dose of the antigen (and adjuvant) are needed to induce a sufficiently strong immune response? How many administrations of the vaccine are needed to induce long-term protection? What is the ideal time interval between the different doses? Can the vaccine be safely administered to young adults? And to more vulnerable populations, such as older adults, children, pregnant women? • Is preceded by pre-clinical research • Different phases: phase 1, 2, 3, 4 • Different designs: o open, single-blind, double-blind, observator-blind o Randomised, controlled (placebo or an alternative, existing vaccine) 5 – 15 years • • • • • • First in Human SAFETY immunogenicity • • • Dose & Schedule finding Safety immunogenicity • • • Efficacy Safety immunogenicity Regulatory submission • Ag definition and purification Formulation selection Immunology in animal models Mechanisms of action Toxicology 5 – 15 years Regulatory submission • Phase 4 & Post-market surveillance Clinical trial phases Safety Immunogenicity Efficacy & effectiveness Overview 1. 2. 3. 4. What is a clinical vaccine trial? Regulation Ethical review board (ERB) Study participants A. B. C. D. Rights and duties Informed consent Liability and insurance Protection of privacy and personal data of the participant A. Reporting adverse events post-vaccination and safety monitoring Blood samples: safety and immunogenicity evaluation 5. Study Design 6. Study Procedures B. 7. Vaccines and vaccine management Declaration of Helsinki ICH/GCP guidelines International Conference of Harmonisation/ Good Clinical Practice • Ethical and scientific quality should be considered when designing, executing, analysing and reporting clinical trials. • The rights, safety and well-being of the study participants as well as the credibility of the study results should be guaranteed. • Careful training of the study team and strict and frequent controls of compliance is performed by study monitors, auditors, inspectors. EU Directive The Clinical Trials Regulation aims to create an environment that is favorable for conducting clinical trials, with the highest standards of patient safety, for all EU Member States. à Belgian law (07 May 2004) based on EU directive. Overview 1. 2. 3. 4. What is a clinical vaccine trial? Regulation Ethical review board (ERB) Study participants A. B. C. D. Rights and duties Informed consent Liability and insurance Protection of privacy and personal data of the participant A. Reporting adverse events post-vaccination and safety monitoring Blood samples: safety and immunogenicity evaluation 5. Study Design 6. Study Procedures B. 7. Vaccines and vaccine management Ethical Review Board • • Based on royal decree of 12 August 1994: o minimum 5 members, males and females, min. 1 general practictioner, half of the members + 1: physicians, min. 1 nurse, a lawyer and an ethicist. Sufficient expertise is important. o More recently: addition of patient representatives Roles of the ERB: o to investigate if the clinical trial does not pose a risk to the subjects, if the investigated drug/vaccine is safe and if it has been sufficiently tested preclinically. o To evaluate the rights of the subjects and if privacy is respected o To evaluate if the rationale of the study is sufficiently supported by scientific data • Besides the ERB, the study documents also have to be submitted to and approved by the Federal Agency of Medicines and Health Products (FAMHP; Federaal agentschap voor geneesmiddelen en gezondheidsproducten, FAGG). • A clinical trial can only start once the ERB and FAMHP have given their approval. • The principal investigator (PI) is responsible for the ERB submission. • The sponsor is responsible for FAMHP submission (PI in case of academic trials). Ethical Review Board Previous Procedure: • In case of a multicenter trial 1 ERB is appointed as ‘central’ (mostly university hospital). This ERB reviews all documents. The other (‘local’) ERBs only evaluate the ICF. New procedure: Implementation of the new Clinical Trials Regulation (EU 536/2014): to simplify and harmonise the submission and evaluation process of CT application across Europe: • Submission via EU portal for all member states • One country-specific and neutral ERB will review all documents Which documents have to be submitted? • ERB advice request form (adviesaanvraagformulier, cfr. separate document) • Study protocol • Investigator Brochure (IB): contains all available information on the investigational product (IP), i.e. chemical composition, preclinical data, clinical data so far, … • Informed Consent Form (ICF) • Recruitment messages (flyers, posters, …) • Other written information that is provided to the subject, e.g. diary cards, memory aids,… Ethical Review Board https://www.uzgent.be/nl/overuz/commissie-voor-medische-ethiek/Paginas/documenten-industriegesponsord-onderzoek.aspx Overview 1. 2. 3. 4. What is a clinical vaccine trial? Regulation Ethical review board (ERB) Study participants A. B. C. D. Rights and duties Informed consent Liability and insurance Protection of privacy and personal data of the participant A. Reporting adverse events post-vaccination and safety monitoring Blood samples: safety and immunogenicity evaluation 5. Study Design 6. Study Procedures B. 7. Vaccines and vaccine management Rights and duties • Participation at a clinical study is always on a voluntary basis (informed consent). • During the entire study period the participant has the right to withdraw from the study (no reason or explanation is needed). • The participant should be present at the study visits on the appointed moments and correctly inform the study team about the use of medication, health status, possible adverse events, (concomitant) participation at other studies, and comply with all procedures. • Non-compliance can lead to exclusion from the study. Informed Consent It needs to be specifically mentioned that participants have the right: • • • • • • • To know that participation is voluntary To ask questions and receive understandable answers before making a decision To know the degree of risk and burden involved in participation To know if there are any benefits involved in participation To withdraw themselves from the project at any time To know how their data will be collected, protected during the project and either destroyed or re-used at the end of the research if plans to reuse the data exist. To know of any potential commercial exploitation of the research Informed Consent • Information and consent form always needs to be written in the language that is best understood by the participant. • Needs to be signed before the very first study procedure is executed • The participant needs to be given sufficient time to ask questions and to consider his/her participation. • Signature of the participant: o ≠ signing a contract o to confirm that participation is voluntary o to confirm that he/she has well understood all aspects of the study and that all questions have been answered o Name, signature, date: have to be hand-written by the participant (not pretyped) • Signature of the study physician: o to confirm that he/she has not exerted any pressure on the subject to participate o to confirm that the participant has been fully informed, and all questions have been answered. • The participant needs to sign first, the physician next. • If needed: witness, parent(s) or guardian Liability and Insurance The commissioning company (sponsor), has a no-fault liability for possible damage inflicted to the participant during the course of the study. It is of no relevance whether this damage is connected directly of indirectly to the participation at the study. ‘No-fault’ means that the participant does not have to demonstrate a fault of the study physician or the sponsor. The sponsor has to take out an insurance policy for this liability. Privacy protection Minimal release of personal data to the sponsor Personally Identifiable Information (PII) Sensitive PII • subset of PII whose unauthorised acquisition, use, modification, loss or disclosure presents a greater risk of harm to the relevant individual. EU GDPR • Global Data Protection Regulation, since 25 May 2018 • Aim: to standardize and strengthen the protection of personal data across the EU • Changes involve: o Significant penalties o Data subject rights § Prior consent § Transparent plain language § Breach notification § Right to access, right of correction, restriction, right to object § Right to be forgotten ßà clinical trials regulation § Data portability o Privacy by design o Data impact assessments o New data protection officers (DPO) Overview 1. 2. 3. 4. What is a clinical vaccine trial? Regulation Ethical review board (ERB) Study participants A. B. C. D. Rights and duties Informed consent Liability and insurance Protection of privacy and personal data of the participant A. Reporting adverse events post-vaccination and safety monitoring Blood samples: safety and immunogenicity evaluation 5. Study Design 6. Study Procedures B. 7. Vaccines and vaccine management Study Protocol • Describes: o o o o o o o o Rationale (Diseases & Vaccine) Objectives & endpoints Study Design Study population Investigational Product Procedures Statistical Methods & cohorts of analysis Administrative matters (record retention, quality assurance, posting of information on publicly available clinical trial registers and publication policy (clinicaltrials.gov) • ‘Manual’ for the conduct of the study • All members of the study team are trained by the sponsor, generally during the site initiation visit (SIV). Study Design • Open, single-blind, double-blind, observator-blind • Randomised, controlled (placebo or an alternative, existing vaccine) Objectives & Endpoints Research objectives describe what we expect to achieve by a project. Endpoint is the quantitative measurements required by the objectives. • Refers to the analyzed parameters • the endpoint for which subjects are randomized and for which the trial is powered. • "Hard" endpoints are well-defined in the study protocol, definitive with respect to the disease process, and require no subjectivity. • "Soft" endpoints are those that do not relate strongly to the disease process or require subjective assessments by investigators and/or patients. Outcome is a final product or end result; consequence; issue. • Refers to the measured variable Patient outcome is the condition of a patient at the end of therapy/intervention or a disease process, including the degree of wellness and the need for continuing care, medication, support, counseling, or education. Study Populations Power calculations and sample size: • How many patients do we need to include in the trial to answer the research question (null hypothesis)? • Null hypothesis: patients with intervention are the same as those without • Alternative hypothesis: patients with interventions are not the same as those without à Type 1 (false-positives, reject H0 when true) and type 2 (false-negatives, accept H0 when false) à Power calculations determine how many patients we need to avoid these errors Inclusion and exclusion criteria • Strictly define the study population • Who can participate and who cannot? • What clinical comorbidities are allowed to be considered ‘healthy’? • What medications are allowed? Subject completion and withdrawal • Screening failure • Subject withdrawal from the study/from the IP at any time 5 – 15 years • • • • • • First in Human SAFETY immunogenicity • • • Dose & Schedule finding Safety immunogenicity • • • Efficacy Safety immunogenicity Regulatory submission • Ag definition and purification Formulation selection Immunology in animal models Mechanisms of action Toxicology 5 – 15 years Regulatory submission • Phase 4 & Post-market surveillance Clinical trial phases Immunogenicity Carefully defined! • Disease specific • Immune respons? Study specific! Immunogenicity Carefully defined! • Immune respons & Type of vaccine (antigen, conjugated…)? Immunogenicity Example: J&J COVID-19 Mechanism: • COVID-19 S-protein = antigen • Packed in adenoviral vector: Viral vector allows mimicking intracellular infection Phase 3 design - Efficacy Phase 3 trial = Efficacy study Gold standard = randomized, placebo-controlled, double blind study • • • • • • • Experimental study (<-> observational study) Formulate the study objective and hypothesis Calculate the sample size < specified parameters and effect size Select a representative target population Execute the study Analyse results (PP and ITT) to define vaccine efficacy Ethical aspects, including GCP PP = Per Protocol / ITT = Intention To Treat Phase 3 design - Efficacy Formulate Null Hypothesis = Study vaccine will NOT provide better protective efficacy as compared to placebo (or active control) 𝛂 is generally set at 0,05 (5%) power (1-𝛃) is generally set at 80-90%, so a type II error of 0.1 Phase 3 design - Efficacy Specify parameter Prespecified, before study start • Significance level 𝛂 : 0,05 (5%) • Power 1-𝛃 : 0,8 or 0,9 (80% or 90%) Unknown parameters (uncertainty) • Standard deviation, intracluster correlation, … • < previous studies, pre-existing data, academic literature Phase 3 design - Efficacy Determine the effect size = The difference in the primary outcome measure used in the sample size calculation that the clinical trial is designed to reliably detect Why is this so important? • Calculated difference < real difference: sample size is too large, ethical problem • Calculated difference > real difference: study is underpowered How is the effect size estimated? • Select a clinically relevant difference • Select a realistic difference based on prior evidence and information • Preferably a combination of both Vaccine impact compared to control depends on • Attack rate of infectious disease • Estimated vaccine efficacy Phase 3 design - Efficacy Define the primary outcome measure – CASE DEFINITION Infection: Clinical symptoms + Laboratory confirmation: • Pathogen detection (culture, PCR, …) • Detection of the pathogen-specific humoral (or cellular) immune response, e.g. seroconversion Severe infection: Clinical symptoms, complications, hospitalisation + Laboratory confirmation Death: All-cause mortality or death causally related to the infection (without any other attributable cause) +/- laboratory confirmation Phase 3 design - Efficacy Compute sample size Formula used will depend on the study design: Superiority, equivalence or non-inferiority trial Sample size: 90 subjects per group or 180 subjects in total (2 arms) Phase 3 design - Efficacy Compute sample size Adjust the sample size to compensate for drop outs Example: Estimate of 10% drop outs (p = 0,1) Adjusted sample size = original sample size 1–p = 180 0,9 = 200 https://www.statsols.com/how-to-use-a-sample-size-calculator Phase 3 design - Efficacy Example - HERALD Phase 3 design - Efficacy Example - CMVictory Phase 3 design - Efficacy Example - CMVictory Phase 3 design - Efficacy What if The effect size is very small (m1-m2) E.g. new vaccine is only slightly more effective than the active control vaccine The event studied is very rare E.g. meningococcal infection (1/100 000) If the development of the event takes a long time E.g. cervical cancer Phase 3 design - Efficacy Select representative study population • • • • • External validity Age Gender Socio-economic status General population or specific groups with increased infection risk Phase 3 design - Efficacy Results analysis Per protocol Only those who completed vaccination according to the protocol Intention to treat All participants who have been randomized and received at least 1 dose of the vaccine Why are both analyses important? Phase 3 design - Efficacy Efficacy and relative risk Phase 3 design - Efficacy Example – AS03 adjuvanted TIV vs TIV Phase 3 design - Efficacy Example – AS03 adjuvanted TIV vs TIV Phase 3 design - Efficacy Ethical aspects • GCP • Maximizing individual benefits and avoiding harm/minimizing risk • Protection of the study participants, e.g. avoid risky behaviour or non-compliance with recommended preventive measures. • SARS-CoV-2 vaccine trial • HIV vaccine trial • Malaria vaccine trial Phase 4 design – Post Marketing Post Marketing studies • • • • • • In vitro studies RCTs Observational studies for safety and effectiveness Impact on outcome (burden of illness) Pharmacoeconomic studies Investigator-initiated research in practice (e.g. in other patient groups) Phase 4 design – Post Marketing Observational studies • • • To study vaccine effectiveness in real world setting (ßà vaccine efficacy in ideal setting of a phase 3 study) Retrospective or prospective Different study designs E.g. Observational studies on COVID-19 vaccination (WHO list): https://www.who.int/publications/m/item/draft-landscape-ofobservational- study-designs-on-the-effectiveness-of-covid-19-vaccination Phase 4 design – Post Marketing Phase 4 design – Post Marketing Case control vs. Cohort Phase 4 design – Post Marketing Test-negative case control study Phase 4 design – Post Marketing Impact studies In case of a very rare event and when vaccination coverage rate (VCR) is high, e.g. MenB vaccination in UK (90% VCR), incidence MenB invasive disease of 0,6/100 000/year, birth cohort of appx. 600 000 live births year in UK Overview 1. 2. 3. 4. What is a clinical vaccine trial? Regulation Ethical review board (ERB) Study participants A. B. C. D. Rights and duties Informed consent Liability and insurance Protection of privacy and personal data of the participant A. Reporting adverse events post-vaccination and safety monitoring Blood samples: safety and immunogenicity evaluation 5. Study Design 6. Study Procedures B. 7. Vaccines and vaccine management Study Protocol • Describes: o o o o o o o o Rationale (Diseases & Vaccine) Objectives & endpoints Study Design Study population Investigational Product Procedures Statistical Methods & cohorts of analysis Administrative matters (record retention, quality assurance, posting of information on publicly available clinical trial registers and publication policy (clinicaltrials.gov) • ‘Manual’ for the conduct of the study • All members of the study team are trained by the sponsor, generally during the site initiation visit (SIV). Study Procedures Conduct of the study o Regulatory and ethical considerations, including the informed consent process o Subject identification and randomisation of treatment o Method of blinding o Outline of study procedures o Informed consent process o Detailed description of study procedures: § ICF § Check Inclusion and exclusion criteria, …. o Biological sample handling and analysis § Biological samples § Laboratory assays: Immunological read-outs and haematology/biochemistry Study Procedures Study vaccines and administration o o o o o o Description of study vaccines Storage and handling Dosage and administration (reconstitution instruction) Contraindications to subsequent vaccination Concomitant medication and vaccines Intercurrent medical conditions that may lead to elimination of a subject to ATP analyses Safety o Solicited local and systemic/general AEs o Serious adverse events (SAE) o AE of specific interest (ex. pIMD - potential immune-mediated disorders) o Pregnancy reporting o (Emergency) unblinding o Stopping rules and safety monitoring Study Procedures Visit 1: Day 0 – Randomization & 1st vaccination Type of contact Time points Check inclusion/exclusion criteria Medical history Physical examination Urine pregnancy test (a) Check contraindications Pre-vaccination body temperature Treatment number allocation(b) Blood sampling for safety assessment (~5.5 mL) Blood sampling for antibody determination and assay development (~20 mL) Blood sampling for CMI response (~20 mL)(c) Vaccine administration Distribution of Diary Cards(d) Recording of AEs Recording of SAEs Recording of pIMDs Recording of pregnancies Record concomitant medication/vaccination(h) Record intercurrent medical conditions requiring medical attention Visit 1 Day 0 O ● O ● O ● ● ● (a) A urine pregnancy test will be performed only for women of childbearing potential. ● ● ● O ● ● ● ● ● ● (b)Treatment number allocation with randomization Study Procedures Study Procedures Intervals between Study Visits Interval Screening (Pre-Day 0) Visit 1 (Day 0) Visit 1 (Day 0) Visit 1 (Day 0) Visit 4 (Day 60) Visit 4 (Day 60) Visit 1 (Day 0) ® Visit 1 (Day 0) Optimal Allowed length of interval interval (a) 5 days 1 – 28 days (b) ® ® ® ® ® ® 7 days 30 days 60 days 7 days 30 days 210 days Visit 1 (Day 0) ® Visit 8 (Day 420) Visit 2 (Day 7) Visit 3 (Day 30) Visit 4 (Day 60) Visit 5 (Day 67) Visit 6 (Day 90) Visit 7 (Day 210) 7 - 9 days 30 - 40 days 60 - 70 days 7 - 9 days 30 - 40 days 210 - 230 days 420 days 420 - 440 days Visits out of range can lead to elimination from ATP analyses. (a) Whenever possible the investigator should arrange study visits within this interval. Overview 1. 2. 3. 4. What is a clinical vaccine trial? Regulation Ethical review board (ERB) Study participants A. B. C. D. Rights and duties Informed consent Liability and insurance Protection of privacy and personal data of the participant 5. Study Design 6. Study Procedures A. Reporting adverse events post-vaccination and safety monitoring B. Blood samples: safety and immunogenicity evaluation 7. Vaccines and vaccine management Safety monitoring eDiary: Electronic (or paper) • Who completes it? o the subject only o Corrections only possible after discussion with participant • Who reviews it? o Investigator or delegate together with the subject o Except: relationship with IP* can only be assessed by a physician • Who signs it? – The investigator/delegate who has reviewed the DiCa must sign and date after review of its content with the subject *IP: investigational product Safety monitoring Solicited Local Adverse Events Solicited adverse events: AE that is expected to occur after vaccination and is asked about in the daily diary Reporting time: • Mostly 7 days after vaccination. Live-attenuated sometimes 14 days Symptoms at injection site = Local AE: • • • • Pain Redness Swelling Induration Grading: • Based on measurements in mm Solicited General Adverse Events Solicited adverse events: AE that is expected to occur after vaccination and is asked about in the daily diary Reporting time: • Mostly 7 days after vaccination. Live-attenuated sometimes 14 days Systemic symptoms = General AE: • • • • • Fatigue Headache Myalgia/ Arthralgia Malaise Fever (Daily T° measurements) Grading: • • • • Mild: easily tolerable Moderate: tolerable, slight disruption of activities, no medical attention Severe: hardly tolerable, total absence of daily activities, may require medical attention Life-threathening Other Adverse Events Unsolicited adverse events: all possible adverse events or changes in the participant’s health condition in addition to the solicited (expected) local and general adverse events. • Medically Attended AE in case of medical assistance needed for AE • Reporting time: 28 days after vaccination Serious Adverse Event is any is undesirable medical event that: – necessitates hospitalization (or extension thereof) – causes persistent or serious disability or makes a person unfit to work – is life threatening – causes death – is a congenital malformation • Reporting time: until end of study – May require follow-up after study end if no other possible cause than vaccine Other Adverse Events AE of Special Interest: • pIMD: Potential Immune Mediated Disease: o A series of adverse events such as auto-immune diseases and other inflammatory or neurological diseases that are not auto-immune strictu sensu, e.g. psoriasis, Crohn’s disease, Multiple Sclerosis, .. • Vaccine Enhanced Diseases: o RSV vaccination in 1967: Natural RSV disease was more severe after vaccination • Other specific to vaccine: o E.g.: Thrombosis with thrombocytopenia syndrome Vaxzevria & J&J COVID-19 vaccine • Reporting time: until end of study AE relation to vaccine Investigators must always assess causality of any AE to the received vaccination. Related to study vaccine? • There is a reasonable possibility that the vaccine caused the AE. o Reasonable possibility means there is evidence to suggest a causal relationship between the drug and adverse event. Suspected adverse reaction means any adverse event for which there is a reasonable possibility that the drug caused the adverse event. Suspected adverse reaction is considered “unexpected” if it is not listed in the investigator brochure or is not listed at the specificity or severity that has been observed. Safety monitoring ‘Stopping rules’ on the basis of the number of adverse events of a certain (defined) severity it can be decided to stop the study at once, either definitively or temporarily. Goal of the study for example: evaluation of different vaccine doses e.g. Staggered design (from low dose to high dose) Data Safety Monitoring Board (DSMB) or Safety Review Committee (SRC) Meetings to evaluate safety data at a certain moment (early in the study). Decides whether the study can be continued or whether the dose can be increased. Staggered design & Sentinel Mainly in first-in-human trials Overview 1. 2. 3. 4. What is a clinical vaccine trial? Regulation Ethical review board (ERB) Study participants A. B. C. D. Rights and duties Informed consent Liability and insurance Protection of privacy and personal data of the participant A. Reporting adverse events post-vaccination and safety monitoring Blood samples: safety and immunogenicity evaluation 5. Study Design 6. Study Procedures B. 7. Vaccines and vaccine management Blood sampling VISITS: V1 / V4 / V7 / V8 Biochemistry COLLECT: PREPARE: RETURN: Humoral Immunity Haematology Blood sampling Day of sampling needs to be carefully defined: • Dependent on immune response o Naïve/ non-naïve subjects? o Humoral immunity? o Cell-mediated immunity? o Innate responses? Overview 1. 2. 3. 4. What is a clinical vaccine trial? Regulation Ethical review board (ERB) Study participants A. B. C. D. Rights and duties Informed consent Liability and insurance Protection of privacy and personal data of the participant A. Reporting adverse events post-vaccination and safety monitoring Blood samples: safety and immunogenicity evaluation 5. Study Design 6. Study Procedures B. 7. Vaccines and vaccine management Vaccine Management Study vaccines are not commercially available • Frequently, a series of preparative steps are required , e.g. mixing of the antigen (liquid or freeze-dried) with a solvent or an adjuvant • Strict control of transportation and conservation conditions • Precise registration: who receives which vaccine (keep correct records) + control of empty boxes or vials following administration o Difficulties of blinding studies: unblinded researchers necessary • Labelling: needs to be done in the three languages (in Belgium), unless the authorities give an exemption • Controlled destruction of remaining vaccines o Study vaccines cannot be used for other purposes GMO & Vaccines • GMO = Genetically modified organism o “Organism of which the genetic material has been altered in such a way that does not occur naturally by reproduction or recombination processes” • Examples: o J&J COVID-19 vaccine & Vaxzevria (AstraZeneca) § Adenoviral vector without natural Adenoviral DNA § Insert COVID-19 Spike protein DNA (reverse transcribed COVID-19 Spike protein RNA) § New organism with altered genetic material –> GMO o Comirnaty (Pfizer) & Spikevax (Moderna) § mRNA of COVID-19 Spike protein § No vector, no ‘organism’ à Not a GMO GMO & Vaccines • Use in humans: Deliberate Release or Contained Use • Deliberate release: o any intentional introduction into the environment of a GMO or a combination of GMOs for which no specific containment measures are used to limit their contact with the general population and the environment o Not possible without first obtaining an authorisation from the competent authority. o case-by-case assessment of the risks to human health and the environment associated with the use of the GMO o Example: J&J COVID-19 vaccine trial: no measures to stop spread to environment • Contained use: o Activities involving GMOs in a "closed environment" such as laboratories, animal units, greenhouses and production units o Example: Poliopolis University of Antwerp, New RSV vaccine candidate in CEVAC: additional measures include tracing of GMO in saliva, stool, semen,…. Cold Chain Management Storage at the investigation site • Vaccines must be stored in a refrigerator approved by the sponsor between 2-8°C for the duration of the study o All refrigerators have been assessed and can be used for storage • Temperatures must be monitored using a device validated by the sponsor o All sites will work with a built-in TMD*. Vaccines should be placed as close as possible to this TMD at all times. • All temperature deviations must be immediately reported to the sponsor o electronic Temperature Deviation Form (eDTF) completed and followed-up by unblinded staff Vaccine Accountability One accountability log per step is available Customized with applicable product, lot number and expiry date Vaccine Labelling Open secondary labels – Example: Study reference Vaccine description, lot, exp date Reconstitution instruction Route/site/side Storage conditions Treatment number Key Notes Clinical (vaccine) trials are highly regulated • ERB, Governments • Closely monitored by several instances, sponsor,DSMB,… • Patient safety and welbeing is as important as scientific purpose Define objectives & endpoints carefully • Protocol = manual • Study outcomes and procedures relevant to these endpoints only