Prevnar IS Safe – Have a Look at the Studies!

March 16, 2009 by
Filed under: Vaccine Science 

In November of 2008, a report was published about a halted vaccine trial in India. Here is an excerpt which can be found on Livemint :

New Delhi: Patient trials of an advanced pneumonia vaccine by the domestic unit of US drug giant Wyeth Inc. have been suspended by India’s drug quality regulator after the death of an infant on whom the vaccine was tested in a trial in Bangalore.
The child had a pre-existing cardiac disorder. Indian drug rules prohibit testing on human subjects with such conditions without the prior approval of the drugs controller general of India (DCGI), the drugs quality regulator.

Indian authorities said that the trial was stopped because:

“The baby was suffering from a cardiac abnormality and should not have been included in the trial at all. It seems that the ‘inclusion-exclusion’ criteria protocol has not been adhered to by the investigator,” said Surinder Singh, drugs controller general. “We have suspended all further trials across the country.”


Inclusion-exclusion criteria exist for two reasons: to protect the participants in the study and to avoid skewing the results of the study. The testers were careless and a baby died; the testers were careless and the results of a study are now questionable. But was there already a problem built into the basic structure of the trial?

Wyeth, the pharmaceutical company which is testing the safety, tolerability and immunogenicity of their advanced pneumonia vaccine, pointed out that the baby who died was in the placebo arm of the study. What was being used as a “placebo”?

Wyeth said the child who died had been administered Prevnar and not the new 13-strain variant.

“The event occurred in the control group, which used the current worldwide standard vaccine for prevention of pneumococcal disease and which has been administered safely more than 200 million times worldwide during the past seven years,” a company spokesperson said in an email. The test was comparing efficacy of Prevnar and the new variant.

Regular readers of Inside Vaccines will know that using a different vaccine as the “placebo” in vaccine safety and effectiveness trials is standard.  It is of particular interest to note that the upcoming PCV13 is being compared to the current 7 valent version, Prevnar. This is the standard method in the U.S. right now as you can see here.

Prevnar (PCV7) was recommended by the CDC in the US in October of 2000.

In the Morbidity and Mortality Weekly Report where the recommendation appeared, the Advisory Committee on Immunization Practices (ACIP) explains how the vaccine was deemed safe (see page 23 of the PDF) here:

Vaccine Safety
Safety of Administration of PCV7 Series Among Infants

Rates and types of adverse events associated with PCV7 administered at ages 2, 4, 6, and 12–15 months are acceptable when compared with the demonstrated benefits of vaccination. In the Northern California Kaiser Permanente efficacy trial, rates of adverse events were compared between children who received PCV7 and those who received the control vaccine (investigational group C meningococcal conjugate). Routine childhood vaccines were administered concurrently with PCV7 and control vaccines.***** To assess vaccine safety, information regarding local and systemic reactions was collected at 48–72 hours and 14 days after each dose. Using telephone interviews, investigators collected adverse-event histories for two subsets of the study population — initially a group receiving DTwP (N = 6,000) and later a group receiving diphtheria toxoid-tetanus toxoid acellular pertussis (DTaP) vaccine (N = 1,500). Frequency of uncommon events requiring medical attention after vaccination was evaluated for the entire study cohort and included emergency room and outpatient clinic visits occurring <30 days and hospitalizations occurring <60 days after receiving the study vaccines.

The full text of the study can be found here. (1)

The FDA licensing papers, here, include a few very small trials where Prevnar was compared to DTaP or to Hib. One of the studies had 80 infants in the Hib group.

On page 26 the FDA states:

The bulk of the safety data regarding local and systemic reactions and other adverse events comes from the NCKP Efficacy study.

Most of the safety data on Prevnar is based on a study comparing one new vaccine, Prevnar with an experimental vaccine, “investigational group C meningococcal conjugate”. What is wrong with this picture?

The Helsinki Declaration states:

32. The benefits, risks, burdens and effectiveness of a new intervention must be tested against those of the best current proven intervention, except in the following circumstances:

* The use of placebo, or no treatment, is acceptable in studies where no current proven intervention exists; or

* Where for compelling and scientifically sound methodological reasons the use of placebo is necessary to determine the efficacy or safety of an intervention and the patients who receive placebo or no treatment will not be subject to any risk of serious or irreversible harm. Extreme care must be taken to avoid abuse of this option.

How could an investigational vaccine be the best current PROVEN intervention? If there was no proven intervention, then why not use a real placebo?

Are the safety studies discussed above what Paul Offit was describing when he said (referring to people like the readers and writers of this blog):

“If they were willing to look at all the studies that were done with vaccines, they would find that they are, I think without question, the safest, best-tested thing we put into our bodies.”

Indeed.

(1) STEVEN BLACK, MD, HENRY SHINEFIELD, MD, BRUCE FIREMAN, MA, EDWIN LEWIS, MPH, PAULA RAY, MPH, JOHN R. HANSEN, BA, LAURA ELVIN, KATHY M. ENSOR, RN, JILL HACKELL, MD, GEORGE SIBER, MD,
FRANK MALINOSKI, MD, PHD, DACE MADORE, PHD, IH CHANG, PHD, ROBERT KOHBERGER, PHD, WENDY WATSON, MD, ROBERT AUSTRIAN, MD, KATHY EDWARDS, MD AND THE NORTHERN CALIFORNIA
KAISER PERMANENTE VACCINE STUDY CENTER GROUP. Efficacy, safety and immunogenicity of heptavalent pneumococcal conjugate vaccine in children. Pediatr Infect Dis J, 2000;19:187–95 Vol. 19, No. 3.

Comments

8 Comments on Prevnar IS Safe – Have a Look at the Studies!

  1. Jupiter on Tue, 17th Mar 2009 12:45 am
  2. Why was an experimental vaccine allowed to be used as a “placebo”
    in a vax safety trial? I’m really curious who, exactly, decided this was an ok way of evaluating vaccine safety.

  3. MinorityView on Tue, 17th Mar 2009 5:41 am
  4. Something that jumped out at me: the exclusion of children with health problems from the study. This only makes sense if they are also excluded from getting the vaccine after it is licensed. Otherwise they test on one group and administer to a different group, right?

  5. jkp on Tue, 17th Mar 2009 8:49 am
  6. On the topic of pneumococcal vaccines, comparison groups and the Declaration of Helsinki, here’s a press release on a trial being done in Finland:

    http://www.rokotusinfo.fi/en/release_090316_html

    Press release 16.3.2009: Vaccine trial violates ethical code
    Finnish NGO: GlaxoSmithKline pneumococcal vaccine trial in Finland violates ethical code

    According to the Finnish NGO “Rokotusinfo ry” (Vaccination Information Association), the London-based pharmaceutical company Glaxosmithkline’s vaccine study in Finland does not comply with the World Medical Association’s Declaration of Helsinki, a central ethical code for medical trials. (1). GlaxoSmithKline is contracting with University of Tampere and the National Institute for Health and Welfare (formerly known as National Public Health Institute on Finland, Kansanterveyslaitos, KTL) vaccine department, and the municipalities’ health care centers. The trial is aiming to recruit one hundred thousand 2-18 months old Finnish children. Vaccination Info association works to promote the dissemination of information regarding vaccination and the promote patient’s rights.
    Violations of the Declaration of Helsinki

    Vaccination Info says GlaxoSmithKline’s pneumococcal vaccine trial seriously violations a central point of the ethical code. According to Declaration of Helsinki, the drug under investigation in the trial should normally be compared to the current best evidence-based treatment or prevention.

    However, in the pneumococcal vaccine trial to be done in Finland, one third of subjects (control group) is to be left without any pneumococcal vaccine. There’s a pneumococcal vaccine on the market which has been approved in 2001 and has been recommended by NPHI’s own task force to be included in the taxpayer-funded vaccine schedule. Instead of the pneumococcal vaccine, the comparison group receives the hepatitis A or B vaccine. These vaccines are not targeted against pneumococcal disease and are normally not considered necessary in Finland for the agegroup.

    The NGO compares the design to a test of new antibiotic against bacteria-induced pneumonia, where one third of patients would only receive malaria medication and no antibiotic, despite an antibiotic medicine on the market with prove effectiveness against pneumonia. Malaria drug does not give any benefit in the treatment of pneumonia, and it has adverse effects, sometimes serious.

    From the view of research ethics, the design of the pneumoccan vaccine trial is the same as the hypotethical antibiotic trial. Hepatitis vaccines are not effective against pneumococcal disease combat, and the package insert of the hepatitis B vaccine lists serious adverse effects, for example neurological effects such as the polio-like Guillain-Barré syndrome, optical nerve inflammation and multiple sclerosis (2).

    According to Rokotusinfo, the vaccine trial also violates other parts of the ethical code. (3).
    Does drug company funding influence vaccine schedule?

    The NGO suspects that pneumococcal vaccine is not included in the vaccine schedule due to the National Public Health Instute’s Vaccine Department’s aim to seek and acquire funding from pharmaceutical companies. For example, in 2007, NPHI’s Vaccine Department received more funding for the pharmaceutical companies as the governmental budget funding. GlaxoSmithKline has been a big source of income for the Finnish NPHI – in both 2006 and 2007, the biggest funding by far came from GlaxoSmithKline. In 2006, GSK funding was 95 percent of the funding from drug manufacturers and 53 percent of the total outside funding for NPHI’s vaccine department. (4)

    National Public Health Institute set in January 2007 two working groups to evaluate whether the rotavirus vaccine and the pneumococcal vaccine should be included in the Finnish taxpayer-funded vaccination schedule. The working groups recommended that both vaccines should be included. Rotavirus vaccine is going to be included in the vaccine schedule in autumn 2009, pneumococcal vaccine is not.

    Pharmaceutical company representatives have publicly indicated (5), that the initiative for the trial has come from researchers at the National Public Health Institue’s (NPHI) vaccine department. Vaccination Info has at September 2008 pointed out NPHI’s press release at that time as a sign of the NPHI “coupling” NPHI’s research funding and the inclusion of new vaccines in the taxpayer-funded vaccine schedule. (6)
    Participation as trial subject not recommended by NGO

    The NGO does not recommend that Finnish families participate in the trial as trial subjects. If the family is seeking protection against pneumococcal disease, they can consider a vaccine which was approved for sale eight years ago. GlaxoSmithKline has also announced that their vaccine is expected to be approved in the coming months. The association however points out that there’s not as much information on the adverse effects of drugs recently come onto the market as there’s for drugs used for a longer period. If the parents want to help advance medical research, they could choose a trial being done ethically. The checklist for parents considering participating in vaccine trial published by the NGO can be used to help. (7)
    Background, sources and more information
    (parts in Finnish for the moment)

    (1) The Declaration of Helsinki is an ethical code first approved in World Medical Association’s meeting in Helsinki in 1964. It is one of the cornerstones of medical research ethics. The declaration has been updated several times since the approval, the latest time was in 2008.

    Adhering to the principles of the Declaration of Helsinki is required by the European Commission’s medical product directive, the Finnish National Public Health Institute’s “Hyvä tutkimustapa Kansanterveyslaitoksessa” code sekä useiden eettisten toimikuntien ohjeistus. Helsingin julistus soveltaa paljolti samoja periaatteita kuin vuonna 1947 Nürnbergin lääkärioikeudenkäynnissä epäeettisesti ihmisillä tehtyjen kokeilujen ehkäisemiseksi vahvistettu ensimmäinen nykyaikainen lääketieteellinen tutkimuseettinen säännöstö, Nürnbergin säännöstö.

    Declaration of Helsinki in Finnish: http://www.laakariliitto.fi/etiikka/helsinginjulistus.html

    Declaration of Helsinki in English: http://www.wma.net/e/policy/b3.htm

    (2) Hepatitis B vaccine package insert (in Finnish): http://spc.nam.fi/indox/nam/html/nam/humpil/5/988095.pdf

    (3) Rokotusinfo: Ethical review of vaccine trials, comparison between the principles of Declarationof Helsinki and the pneumococcial trial(s) ongoing and to be done in Finland

    http://www.rokotusinfo.fi/rokotetutkimus/eettinen_arviointi_html

    (4) Funding for NPHI of Finland for years 2006 and 2007: http://www.rokotusinfo.fi/tekstit/ktl_roko_rahoitus_2007_html

    (5) Hufvudstasbladet 16.9.2009, Petteri Knudsen & Taneli Puumalainen

    “Både den planerade pneumokock- och den pågående HPV-vaccinundersökningen är initierade av Folkhälsoinstitutets forskare som behöver beslutsunderlag för en nationell vaccinationsstrategi.”

    (6) Rokotusinfo ry: release 28.9.2009, “KTL:n rokoteosasto lääkeyhtiöiden leivissä – tiedotus uusista rokotteista ei perustu näyttöön”, http://www.rokotusinfo.fi/yhd/tiedotteet/tiedote_080928_html

    (7) Rokotusinfo: A checklist for persons considering to become trial subjects, http://www.rokotusinfo.fi/rokotetutkimus/muistilista_html

    Information on organizations and persons resposible for design out, carrying out, approving and supervising the trial(s)

    Persons responsible for the trial as per Finnish research legislation

    Head of vaccine department Terhi Kilpi, The National Institute for Health and Welfare

    http://www.thl.fi/ (see also http://www.finip.f)

    Professor Timo Vesikari, University of Tampere, head of the vaccine research center at University of Tampere Medical School

    http://www.uta.fi/rokotetutkimuskeskus/

    Supervisory authority

    Oversight of vaccine trials: National Agency for Medicines

    http://www.nam.fi

    Ethical review

    Hospital district of Helsinki and Uusimaa coordinating ethical review board (Helsingin ja Uudenmaan sairaanhoitopiiri, koordinoiva eettinen toimikunta)

    Hospital district of Helsinki and Uusimaa ethical review boards: http://www.hus.fi/default.asp?path=1,28,2530,15595,2540

    Pirkanmaa hospital district ethical review board (Pirkanmaan sairaanhoitopiirin eettinen toimikunta)

    http://www.tays.fi/default.aspx?nodeid=10079&contentlan=1

    Sponsor

    Medical director Petteri Knudsen (GlaxoSmithKline)

    Taneli Puumalainen, medical advisor (GlaxoSmithKline, also researcher at National Institute for Health and Welfare, source: personnel search of the Institute)

    The topic is also covered in releases:

    * (21.2.2009) Tiedote: Räikeää epäeettisyyttä rokotetutkimuksessa
    * (12.2.2009) Tiedote: KTL:n pneumokokkirokotetutkimus arveluttava
    * (28.9.2008) Tiedote: KTL:n rokoteosasto lääkeyhtiöiden leivissä – tiedotus uusista rokotteista ei perustu näyttöön – vuonna 2007 KTL:n rokoteosasto sai lääkeyhtiörahoitusta n. 35 % enemmän kuin budjettirahoitusta.
    * (9.9.2008) Tiedote: Suomalaisia värvätään laajoihin rokotetutkimuksiin

  7. MinorityView on Fri, 20th Mar 2009 6:15 pm
  8. http://www.reuters.com/article/rbssBiotechnology/idUSN2744286420081027

    “Wyeth (WYE.N) on Monday said trials of an improved form of its blockbuster Prevnar vaccine suggest it is as safe as the original and may offer broader protection against infections in infants and young children.”

    As safe as the original…which was tested against the unknown safety profile of an experimental vaccine…everyone feel really, really safe?

  9. wallacesmum on Sun, 28th Jun 2009 11:17 pm
  10. The thing about the Helsinki Declaration is that someone arguing for “good” testing is damned either way. As Jupiter and the author point out, the default “placebo” for a vax trial is the existing vax, which is a-ok with TPTB. The only problem here is that they used the wrong vax as placebo (I love the sincere and sanctimonious outlining of the risks associated with HepB – where’s that conversation during the HepB trials?). We have to go back to the first shoddy trials, and show how crappy those are, and THEN talk about how all the subsequent trials are based on this sham.

    […] – En Inde, un enfant est décédé au cours des essais cliniques pour le vaccin Prevnar 13 de Wyeth. Wyeth a prétexté que le décès avait eu lieu dans « le groupe placebo » mais le « placebo » n’était autre que l’ancienne version du Prevnar (Prevnar 7) dont les effets secondaires  graves y compris mortelsne sont pas si rares que ça comme le révèlent de nombreux témoignages francophones qui pullulent sur internet! […]

    […] En Inde, un enfant est décédé au cours des essais cliniques pour le vaccin Prevnar 13 de Wyeth. Wyeth a […]

    […] En Inde, un enfant est décédé au cours des essais cliniques pour le vaccin Prevnar 13 de Wyeth. Wyeth a […]

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