Vaccine Pharmacovigilan

ce

Rajiv AhlawatDepartment of Pharmacy Practice, NIPER, Mohali

Vaccination is the top Public

Health achievement of

the 20th Century

MMWR 1999; 48:241

Vaccine-Preventable Diseases:Baseline 20th Century & Current Morbidity

Number of Cases Disease Baseline 2010* % Decrease Smallpox 48,164 0 100.00 Diphtheria 175,885 0 100.00 Measles 503,282 57 99.99 Mumps 152,209 2,528 98.34 Pertussis 147,271 21,291 85.54 Polio (par.) 16,316 0 100.00 Rubella 47,745 6 99.99 CRS 823 0 100.00 Tetanus 1,314 8 98.39 Hib 20,000 16 99.92

MMWR 1999;48:245, 2011;59:1700

Vaccine provide by Govt. of India

Govt. of India is providing vaccination to prevent 7 vaccine preventable diseases(VPDs)namely,

– Diphtheria, – Pertussis, – Tetanus, – Polio, – Measles, – Hepatitis B – BCG– JE vaccination– Hib (given as pentavalent containing Hib+DPT+Hep B)

Other vaccines….

• Pneumococcal vaccine• Rotavirus vaccine• Hepatitis A• MMR• Influenza• Meningococcal• Cholera• JE• HPV• Varicella • Typhoid

Definition

• According to the CIOMS/WHO Working Group on Vaccine Pharmacovigilance,Vaccine pharmacovigilance is defined as “the science and activities relating to the”

– Detection, – Assessment, – Understanding and – Communication of adverse events following immunization and other vaccine- or immunization-related issues, and to the prevention of untoward effects of the vaccine or immunization”

Importance of Vaccine Safety• Decreases in disease risks and increased

attention on vaccine risks• Public confidence in vaccine safety is critical• Low tolerance for vaccine risks

– Higher standard of safety is expected– Vaccinees generally healthy (vs. ill for drugs)– Lower risk tolerance = need to search for

rare reactions

Steps of vaccine Pharmacovigilannce

Test hypothesis through appropriate epidemiological methods

Develop hypothesis about causal association between an AEFI and vaccination

Detect signal Suggesting AEFI is related to vaccine

Which AEFIs should be reported?• Serious AEFI• Signal and events associated with newly introduced

vaccine• AEFI that may have been caused by an immunization

error• Significant events of unexplained cause occurring

within 30 days after a vaccination• Events causing significant parental or community

concern• Swelling, redness, soreness at the injection site IF it

lasts for more than 3 days or swelling extends beyond nearest joint

Adverse event following immunization (AEFI)

• Vaccine product-related reaction– Extensive limb swelling following DTP vaccination.

• Vaccine quality defect-related reaction– Failure by the manufacturer to completely inactivate a lot of

inactivated polio vaccine leads to cases of paralytic polio • Immunization error-related reaction

– Transmission of infection by contaminated multidose vial• Immunization anxiety-related reaction

– Vasovagal syncope in an adolescent during/following vaccination • Coincidental event

– Example: A fever occurs at the time of the vaccination (temporal association) but is in fact caused by malaria.

Types of ADR

• Very common ≥ 10% • Common (frequent) ≥ 1% and < 10% • Uncommon (infrequent) ≥ 0.1% and < 1%• Rare ≥ 0.01% and < 0.1% • Very rare < 0.01%

Determining causality

Difficulties in determining causation between events that are linked in time are common to all drug and vaccine safety monitoring systems. This is particularly challenging in the case of vaccines, because:• Information on “dechallenge and rechallenge” is usually missing,• Vaccines are given to most of the country’s birth cohort at an age

when coincidental disease are likely, Several vaccines are likely to be administered at the same immunization visit,

• Vaccine storage, handling, transport and administration must adhere to specific conditions.

• Any of these, if not done correctly, can result in an adverse event. The possibility of immunization errors therefore must be investigated.

Rate of ADR occurrence

• Observed rate– Total number of cases reported per 1000 vaccinated children– Detect in clinical trial or post licensure vaccine safety

• Background rate– Not related to vaccine– Occur per 1000 unvaccinated children– Record prior or simultaneously to vaccination

• Vaccine reaction rate– Related to vaccine– Detected in placebo controlled randomized clinical trial, or passive

surveollance or post licensure studies – Observed rate – background rate

Other factors to consider when comparing rates of AEFIs

• Vaccines Manufaturer• Age- child vs adloscents• Vaccine dose- primary vs booster• Case definition- standard• Surveillance method- method of surveillance• Background condition-background rate of

certain events may differ between communities

ProblemImagine that rumours begin to circulate about a vaccine when cases of convulsions following immunization occur amongst vaccinated infants. The background rate of convulsions in this population is 1:1,000 infants. The observed rate in vaccinated infants is 1.2:1,000. What is the vaccine attributable rate derived from these figures?

– A. 2 additional cases of convulsions in every 1,000 vaccinations, compared with the background rate.

– B. 2 additional cases in every 10,000 vaccinations, compared with the background rate.

– C. 1.2 additional cases in every 1,000 vaccinations, compared with the background rate.

– D. 1.2 additional cases in every 10,000 vaccinations, compared with the background rate.

Rotavirus vaccine• Pre-licensure literature noted a suspicion of an increased risk

of intussusception. • After RotaShield® was licensed for routine use by the public

(approximately one million children vaccinated within the first nine months licensure) the American vaccine safety surveillance, Vaccine Adverse Event Reporting System (VAERS), began to receive reports of intussusception following administration of the vaccine.

• About 100 (0.01%) of the one million children vaccinated developed intussusception, 16 a potentially life-threatening bowel obstruction that occurs for unknown reasons in about one child per 10 000, regardless of whether or not they have received a vaccine.

Because of the uncertainty about the relationship between RotaShield® and intussusception cases following vaccination, the manufacturer voluntarily took the product off the market in 1999.

Risk of acquiring illnesses following infection versus risk following vaccination

Source for vaccine safety

Risk/benefit assessment

• Required to strengthen the confidence in immunization programmes.

• Address the population at risk (not the individual at risk),• Take into account contextual issues (economics, availability of

alternative vaccines, sociopolitical and cultural factors),• Be prompted by a newly identified risk, but must remain

holistic (e.g. take into account the entire safety profile of a vaccine, not only the specific information relating to the event that was detected),

• Run in parallel to active enquiry, cooperation and exchange of information.

Problem

During a mass measles campaign for 7.5 million children aged from 9 months to 14 years, a 7 year old child developed encephalopathy, convulsions and died.

– Should the measles campaign be suspended?– Does the need for action to protect children from

possible vaccine related harm in this situation outweigh the need for further investigation, or vice versa?

Options for action could include discontinuing the immunization campaign, withdrawing a vaccine batch, and improving staff training and communication.Withdrawing a vaccine lot:

– Advantages: reduces fear of vaccine, renews confidence in the vaccine or the campaign,

– Disadvantages: cost, potential compromise of the campaign, loss of confidence in vaccine quality.

Audit injection practices of health workers to identity sources of immunization errors; investigate the need for improved training and education.It is essential to indicate the quality and quantity of any future evidence necessary to trigger reconsideration of the issue, and how the outcomes of any actions will be monitored and assessed.

Risk benefit evaluation• In the country of Kanindistan, there are 5 million children

between the ages of 1–5, and the annual mortality in this age group is 120/100,000.

• In a mass vaccination campaign, all suitable children between the ages 15 years are to be vaccinated against Japanese Encephalitis Virus (JEV). Three million children have been vaccinated in the first 2 weeks, during which 140 deaths have been reported following vaccination.

• In the year before the vaccination campaign the risk of children in the same age range dying of naturally acquired JEV infection was 5.25/100,000.

Evaluate this information, to determine whether the risk/benefits of the JEV vaccination campaign outweigh the risks of the disease.

Comparing mortality rates of unvaccinated vs. vaccinated children.

• With 3 million children vaccinated, the expected mortality in this group in a 2 week period is:3,000,000 x 120/100,000 x 2/52 = 138

• The number of deaths (140) is slightly higher than this figure.

Comparing the risk of children dying from Japanese Encephalitis (JE) with the excess

mortality among vaccinated children.

• (140 – 138) / 3,000,000 = 1/1,500,000 vaccinated children.

• The risk of dying from the disease (5.25/100,000) is greater than the excess mortality associated with the vaccination (1/1,500,000).

Problem• The country of Rubovia has a population of 60

million and the annual incidence of Guillain Barre syndrome is 2/100,000 individuals.

• In an immunisation campaign, 5 million adults were immunised with an influenza A vaccine. In the 8 weeks following immunisation 26 of them developed Guillain Barre syndrome.

Calculate the vaccine attributable rate of Guillain Barre syndrome per 100,000 immunised individuals.

The expected incidence of Gullain Barre syndrome in a population of 5million people in an 8 week period is:

5,000,000 x 2/100,000 x 8/52 =16 (15.4)

The number observed is 26, therefore the excess is 26 – 16 = 10The excess incidence is 10/5,000,000 = 0.2/100,000 vaccinated individuals.

Role of disease burden studies in the development and introduction of new and underutilized vaccines

Disease-Burden Studies

Disease Epidemiology• Geographical distribution• Age groups• Seasonality, risk factors

Vaccine Design

Clinical Evaluation• Study sites• Vaccination schedules & Strategies

Vaccine Utilization• Target groups• Impact• Cost-effectiveness

Clinical trials and assessment of vaccine safety

Steps on Vaccine Development1

• Recognize the disease as a distinct entity

• Identify etiologic agent

• Grow agent in laboratory

• Establish in animal model for disease

• Identify an immunologic correlate for immunity to the disease- usually

serum antibody

• Inactivate or attenuate the agent in the laboratory- or choose antigens

• Prepare candidate vaccine following GOOD manufacturing Procedures

• Evaluate candidate vaccine(s) for ability to protect animals

Steps on Vaccine Development2

• Prepare protocol(s) for human studies

• Apply to MCC for investigational New drug (IND)

approval

• Phase I human trials- Safety and immugenicity,

dose response

• Phase II trials- Safety and immugenicity

• Phase III trials- Efficacy

Steps on Vaccine Development3

• Submit Product Licensure Application MCC approval

• Advisory Committees review and make recommendations

• Marketing Post- Licensure Surveillance for safety and effectiveness

(Phase IV)

• Long and Complicated process

Usually takes 10-15 years

Many vaccine candidates fail for every success

Costs: $ 100- $ 700 million per successful vaccine

Vaccine Evaluation

Pre-licensingRandomised, Blinded, Controlled Clinical Trials

Vaccine efficacy: Protective Effect under

Idealised Conditions

RCT: controlled experiments, simple interpretation

Post-licensing Observational Studies

Vaccine effectiveness: Protective Effect under

Ordinary Conditions of a public health programme

prone to bias, more complex interpretation

Basic Calculation of VE

% reduction in attack rate of disease in vaccinated (ARV)

compared to unvaccinated (ARU) individuals

VE (%) = (ARU-ARV) X 100 ARU

Where

and

Consequently, VE = 1-RR (preventive fraction)

ARU

ARU1

ARV

ARURR

0,9 – 0,2

0,9 VE = = 78%

Vaccinated

IV = 2/10 = 0,2

IU = 9/10 = 0,9

Unvaccinated

Basic Calculation of VE

Methods to Assess VE

• Pre-licensure: Randomised control trial (RCT)

• Post-licensure:

Observational/Field investigation • Screening method

• Cohort study

• Household contact study

• Case-control study

Observational study: Screening Method

• Used with Routine Surveillance Data Take population vaccine coverage (PPV)

Compare with coverage in cases (PCV)

VE = 1 - PCV x (1-PPV) (1-PCV) x PPV

Sample Sizes Needed During Clinical Trials to Detect Increases in Rates of

Rare Vaccine Adverse Events

Rates of Event (%) Sample Size* No. Potentially Affected Annually1

0.1 vs. 0.2 50,000 4,000

0.1 vs. 0.3 17,500 8,000

0.05 vs. 0.1 100,000 2,000

0.01 vs. 0.02 500,000 400

0.01 vs. 0.03 175,000 800

* Two-arm, power=80%, alpha (2 sided)=5% 1 If the entire birth cohort (approx. 4 million children) received the vaccine each year

Adapted from Ellenberg SS: Safety considerations for new vaccine development. Pharmacoepidemiol Drug Safety 10(5):411-5, 2001

Vaccine Rare ADRs

Oral polio vaccine (OPV) VAPP very rare (0.0002% – 0.0004% or 2 – 4/1,000,000)

Measales Febrile seizure (uncommon at 0.3% or 1/3000)Thrombocytopenic purpura(very rare at 0.03% or 1/30,000)

BCG Fatal dissemination of BCG infection (very rare at 0.000019% – 0.000159% or 0.19 – 1.56/1,000,000)

IPV Not Known

Haemophilus influenzatype b conjugate (Hib)

Not Known

Pneumococcal conjugate, (PCV-7), (PCV-10) Not Known

Hepatitis B (HepB) Not Known

Inactivated polio vaccine (IPV) Not Known

Rotavirus Not Known

Vaccine safety . Safety profile of vaccine. https://extranet.who.int/vaccsafety/en/vaccine/learning/learning/module1/index.html. Accessed on 13 March 2012.

Vaccines are Not Without Risk

• No vaccine is 100% safe • No vaccine is 100% effective• All vaccines have possible side effects, most mild, rarely

severe • The risk of disease far outweighs the risk of vaccine

The Provider’s Role• Immunization providers can help to ensure

the safety and efficacy of vaccines through proper:–vaccine storage and administration–timing and spacing of vaccine doses–observation of precautions and

contraindications

The Provider’s Role• Immunization providers can help to ensure

the safety and efficacy of vaccines through proper:–management of vaccine side effects– reporting of suspected side effects to

VAERS–vaccine benefit-risk communication

Precaution

• A condition in a recipient which may increase the chance or severity of an adverse event, or

• May compromise the ability of the vaccine to produce immunity

Invalid Contraindications to Vaccination

Mild illness Mild/moderate local reaction or fever

following prior dose Antibiotic therapy Disease exposure or convalescence Pregnancy in the household Premature birth Breastfeeding Allergies to products not in vaccine Family history unrelated to

immunosuppression

Vaccine-Associated Paralytic Polio (VAPP) OPV is a live attenuated virus

1 out of 2.4 million doses VAPP

1997 a IPV/OPV schedule

2000 an all IPV schedule recommended in US

Thank you

• Hib (given as pentavalent containing Hib+DPT+Hep B)

• DPT (Diphtheria, Pertussis and Tetanus Toxoid)