Benefit-Risk assessment of vaccines, the perspective of a European regulatory agency

Perspective on Benefit-Risk Decision-making in Vaccinology Les Pensières Fondation Mérieux Conference Center www.pei.de 23-25 June 2014 Benefit-Risk assessment of vaccines, the perspective of a European regulatory agency Christoph Conrad Paul-Ehrlich-Institut Paul-Ehrlich-Strasse 51-59 63225 Langen GERMANY +49 (0) 6103 77 1050 +49 (0) 6103 77 1234 E-mail: christoph.conrad@pei.de Homepage: http://www.pei.de

Benefit-Risk evaluations are at the heart of decisionmaking in the regulation of medicines clinical development licensing postmarketing 2

AMG (Medicinal Products Act) 4: Definition (28) The risk-benefit balance is an assessment of the positive therapeutic effects of the medicinal product in relationship to the risk referred to in sub-section 27 letter a, and in the case of medicinal products intended for use in animals, also referred to in sub-section 27 letter b. (28) Das Nutzen-Risiko-Verhältnis umfasst eine Bewertung der positiven therapeutischen Wirkungen des Arzneimittels im Verhältnis zu dem Risiko nach Absatz 27 Buchstabe a, bei zur Anwendung bei Tieren bestimmten Arzneimitteln auch nach Absatz 27 Buchstabe b. 3

Risk: Definition AMG (Medicinal Products Act) 4 (27) A risk linked to the use of a medicinal product is: a) any risk to patients health or public health linked to the quality, safety or efficacy of the medicinal product and, in the case of medicinal products intended for use in animals, any risk to human or animal health, b) any risk of adverse effects on the environment. (27) Ein mit der Anwendung des Arzneimittels verbundenes Risiko ist a) jedes Risiko im Zusammenhang mit der Qualität, Sicherheit oder Wirksamkeit des Arzneimittels für die Gesundheit der Patienten oder die öffentliche Gesundheit, bei zur Anwendung bei Tieren bestimmten Arzneimitteln für die Gesundheit von Mensch oder Tier, b) jedes Risiko unerwünschter Auswirkungen auf die Umwelt. 4

AMG (Medicinal Products Act) 40: Clinical Trials the foreseeable risks and inconveniences are medically justifiable, compared with the benefit for the person on whom the clinical trial is to be conducted (person concerned), and the anticipated significance of the medicinal product for medical science,...die vorhersehbaren Risiken und Nachteile gegenüber dem Nutzen für die Person, bei der sie durchgeführt werden soll (betroffene Person), und der voraussichtlichen Bedeutung des Arzneimittels für die Heilkunde ärztlich vertretbar sind,... 5

Benefit-risk balance Both benefits and risks are balanced against each other, i.e. judged in the relative importance Inherently difficult because very different outcomes/effects may have to be balanced Moving target in clinical development Benefit-risk evaluation is not a static but a dynamic process Benefit-risk balance changes with accumulating data Benefit-risk balance changes with different stage of development and may change also after marketing authorization Remark: The term Benefit-risk-ratio is not meaningful 6

Benefit-risk balance postmarketing Example: Benefit-risk balance in case of a new finding of a potential adventitious agent previously unrecognized 7

Knowns and unknowns There are known knowns. These are things we know that we know. There are known unknowns. That is to say, there are things that we now know we don t know. But there are also unknown unknowns. These are things we do not know we don t know. Donald Rumsfeld Known knowns: favorable or unfavorable effects Known unknowns: uncertainties Unknown unknowns: 8

Background Porcine circovirus DNA in rotavirus vaccines in 2010 New technologies may detect agents that previous methods were not capable of Recommendation from ECBS and ICDRA: WHO to assist countries in developing a risk assessment process subsequent to marketing authorization A broad regulatory framework exist pre-licensure But a few aspects associated with findings, discovered subsequent to marketing authorization are not well defined, in the sense of regulatory actions and decision-making 9

Scope and Purpose To provide an overview of the principles related to the scientific assessment of risk with any new finding of a potential adventitious agent in an already registered biological product. To assist regulators in the considerations they might include during the evaluation and decision-making process. It does not cover: Risk assessments performed by the manufacturer Guidance on the decisions taken by health care officials (NITAGs) Guidance on GMP compliance and subsequent decisions/actions 10

Regulatory risk evaluation process 11

Re-evaluation & New Benefit / Risk Re-evaluation of: Quality / non-clinical / clinical data Post-marketing data (phase IV, pharmacovigilance) Communication with the Inspectorate New benefit/risk assessment Process which largely depends on: Type of adventitious Agent Type of product and Indication Communication with public health officials (NITAGs) 12

Outcome of benefit risk project in licensing (EMA) B/R are balanced intuitively; a matter of judgement Distinct separation of the B/R elements to: Favourable effects Unfavourable effects Uncertainty of favourable effects Uncertainty of unfavourable effects 13

Example (hypothetical) Benefits Risks N ame Descript ion Unit Placebo 300 mg Progressionfree survival Hazard Ratio Progressionfree survival (median) Objective Response (RECIST) Diarrhoea CTC3 Grade 3-4 QTc related events CTC 3 Grade 3-4 Infections CTC 3 Grade 3-4 Date of randomization to the date of objective progression or death Date of randomization to the date of objective progression or death (Weibull model) Proportion of complete or partial responders (at least a 30% decrease in the sum of the longest diameter from baseline) Increase of 7 stools per day over baseline; incontinence; IV fluids 24 hrs; hospitalization; QTc >0.50 second; life threatening signs or symptoms (e.g., arrhythmia, CHF, hypotension, shock syncope); Torsade de pointes IV antibiotic, antifungal, or antiviral intervention indicated; ; Lifethreatening consequences (e.g., septic shock, hypotension, acidosis, necrosis) unitless 1 0.46 Only a very low number of patients with definite RET negative status at baseline months 19.3 30.5 % 13 45 Uncertainties Reference in the text From Weibull model distributional assumptions probably do not hold Not a good surrogate. May provide some symptom relief (assumed) Major Objection No. 1, Discussion on Clinical Efficacy (page 44) % % 2.0 1.0 10.8 13.4 Duration of follow up in the pivotal study is quite short with regard to the need for long duration of treatment and therefore the risk of developing further major Cardiac SAEs including Torsades de pointe. Could the risk be underestimated? How well can oncologists monitor in clinical practice? Major Objection No. 2, Discussion on Clinical Safety (page 65), Scientific Advisory Group answers to CHMP See RMP % 36.4 49.8 Discussion on Clinical Safety (page 66) 14

B/R assessment methodology in case of Porcine circovirus DNA in rotavirus vaccines an example Based on EMA Benefit-Risk Methodology Project CHMP assessment report template Four-fold qualitative model Favourable effects Uncertainty of favourable effects Unfavourable effects Uncertainty of unfavourable effects 15

Clinical benefits of Rotavirus Vaccines are established Recognized medical need In clinical trials: Demonstrated protection against RV gastroenteritis (GE) Across circulating RV strains In various settings (epidemiologic, socio-economic, ) Demonstrated impact on reduction of hospitalisations related to RVGE Safe and immunogenic in special populations (HIV+, preterm) Persistence of protection over 3 years Effectiveness and impact studies (including reduction of diarrhearelated mortality) Confidence on benefit has increased since license (decreased uncertainty of favourable effects) 16

B/R assessment methodology in case of Porcine circovirus DNA in rotavirus vaccines an example Based on EMA Benefit-Risk Methodology Project CHMP assessment report template Four-fold qualitative model Favourable effects Uncertainty of favourable effects Unfavourable effects Uncertainty of unfavourable effects 17

Safety Profile of Rotavirus Vaccine is Similar to Placebo Serious adverse events occurred at similar rates compared to placebo, significantly fewer SAEs associated with GE disease in Vaccine vs placebo (pooled studies) Safety meta-analysis: Solicited adverse events occurred at similar rates in Vaccine and placebo recipients Unsolicited adverse events more frequently observed in Vaccine recipients are diarrhea, abdominal pain, flatulence, dermatitis and irritability No increased risk of intussusception compared to placebo: controlled safety study 18

B/R assessment methodology in case of Porcine circovirus DNA in rotavirus vaccines an example Based on EMA Benefit-Risk Methodology Project CHMP assessment report template Four-fold qualitative model Favourable effects Uncertainty of favourable effects Unfavourable effects Uncertainty of unfavourable effects 19

Potential unforeseen risks linked to the presence of PCV1 in Rotavirus Vaccine Fact: PCV1 DNA has been found in Rotavirus Vaccine Risk of PCV1 being pathogenic in humans Fact: no AEs typical of PCV1 have been seen in safety database Risk of PCV1 being infectious in humans Risk of safety issue from PCV-1 in Risk of PCV1 replicative virions in vaccine Risk of PCV1 replication in human gut Infants may react differently to PCV1 infection Fact: ingestion of PCV1 is common in adults and older children, although not pathogenic 20

Risk of PCV-1 being infectious in humans Clinical sample testing from Vaccine recipients Currently available data do not suggest occurrence of PCV-1 infection PCV has been reported as not infecting humans, although the exposure level from food is thought to be high (Li et al., 2010) Absence of anti-pcv-1 Abs in human serum in most reports (Allan et al. (1994),Todd et al. (2001), Tischer et al. (1995)) No evidence of PCV infection in patients receiving xenotransplants of pig tissue (Garkavenko et al., 2004) No evidence of circoviruses in a range of human tissues from >168 immunocompromised adults (presumed dietary exposure through meat) (Hattermann et al., 2004b) 21

Risk of PCV-1 being pathogenic in humans 5. Adverse reactions in the short-medium term? No signals in clinical and post-marketing data No evidence of PCV-related pathogenicity in humans exposed to pork meat or swine => LOW PROBABILITY 6. Could PCV-1 DNA integrate into the genome of vaccine recipients? No reported evidence of PCV integration into host DNA simple, circular genome makes this highly unlikely (Peden 2001) => LOW PROBABILITY 7. Could PCV-1 cause long-term health problems in vaccine recipients (i.e. infants)? Not pathogenic in children from pork-consuming age No safety signal within first 2-3 years post-vaccination => LOW PROBABILITY 22

Exposure to PCV-1 through other sources PCV-1 detected in commercial products including veterinary vaccines: a common event PCV1 DNA detected in commercial pepsin but no infectivity in inoculated PK-15 cells or in inoculated pigs (Fenaux et al., 2004) PCV-1 DNA detected in 11% (2/18) of the commercial porcine vaccines on the market (Quintana et al., 2005) PCV frequent in pork products (Li et al., 2010) Exposure of infants to PCV-1 not documented, however potential sources of exposure include products from porcine origin and/or products that use porcine extracts in the manufacturing cycle, examples: Powder milk (use of food grade pork trypsin in manufacturing) Surfactants from pork origin used to treat neonatal respiratory distress syndrome (RDS) Pork gelatin as food additive Pancreatic Enzyme Replacement Therapy: used in the treatment of exocrine pancreatic insufficiency. Extracted from pigs glands 23

Semi-quantitative risk assessment Probability of impact Size of impact Probability of intact virus present in Rotavirus Vaccine Probability of it being infectious in humans Probability of PCV1 being pathogenic in humans Overall probability of impact Likelihood of impact not seen with 3 year safety data Likelihood of impact not seen in children from porkconsuming age Overall size of impact high low low low low low low Probability of impact * Size of impact = Risk low 24

Rotavirus Vaccine Benefit/Risk is Positive remains Presence of PCV-1 RV leading cause of severe childhood diarrhea Vaccination only known effective preventative strategy Widespread use of rotavirus vaccines can prevent about 2 million deaths over next decade (NEJM 2010:362;4) Safety data from clinical trials and post-marketing reflects presence of PCV Potential unforeseen risks linked to PCV are low Benefit/risk for Rotavirus vaccine remains favorable 25

Acknowledgements Paul Ehrlich Institut Dr. Jan Müller-Berghaus Dr. Michael Pfleiderer 26

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