Tag: clinical trials

Is the MMR Vaccine Licensing Being Called into Question?

Why do some folks think that the MMR vaccine licensing is being called into question?

Yup. That’s what the usual suspects are trying to make you think.

Is the MMR Vaccine Licensing Being Called into Question?

Taking advantage of the fact that many sites publish all press releases, these folks want you to think that a major news site is following their latest bombshell, which of course is just another dud.

The MMR was licensed in 1971. The ICAN papers are from 1978…

You mean there really isn’t an FDA coverup?

“Clinical studies of 284 triple seronegative children, 11 months to 7 years of age, demonstrated that M-M-R II is highly immunogenic and generally well tolerated.”

MMR II Package Insert

Not only is the package insert very transparent about the studies used to approve the MMR II vaccine they are talking about, since only a minor change was made to the original MMR vaccine, which was approved in 1971, it isn’t surprising that larger trials weren’t required at the time.

So there were earlier, larger trials?

Yup.

But did they use a saline control group?

Nope.

A Vaccinated vs Unvaccinated Study - Stokes et al on Trivalent combined measles-mumps-rubella vaccine. Findings in clinical-laboratory studies.
A Vaccinated vs Unvaccinated Study – Stokes et al on Trivalent combined measles-mumps-rubella vaccine. Findings in clinical-laboratory studies

The control group was actually unvaccinated.

It is also important to keep in mind that this study, and a few other MMR studies, followed much, much larger studies of the individual measles, mumps, and rubella vaccines.

“The large majority of children in the United States have been vaccinated against measles and a sizable portion have been given mumps and rubella vaccines. It is estimated by us based on vaccination distribution that about 41 million children have received measles vaccine, 7 million mumps vaccine, and 21 million rubella vaccine. The combined triple vaccine provides a simple, safe, and effective immunization procedure using a single vaccine dose against three important diseases in children who have not yet been immunized.”

Stokes et al on Trivalent combined measles-mumps-rubella vaccine. Findings in clinical-laboratory studies.

Much larger double-blind, placebo-controlled studies of the individual measles, mumps, and rubella vaccines.

This is why you don’t routinely do vaccinated vs unvaccinated studies anymore. It is unethical to let kids get measles, mumps, rubella or other diseases.

The bottom line is that the measles (1968), mumps (1967), and rubella (1969) vaccines were safe when they were approved by the FDA.

The MMR (1971) was safe when it was approved by the FDA.

And MMR-II (1978) was safe when it was approved by the FDA.

Since then, there have also been studies showing that getting a second dose of MMR-II is safe and effective and that ProQuad, the combination measles, mumps, rubella, and chickenpox vaccine is safe and effective, although it is associated with a small increased risk of febrile seizures if given as a first dose.

There is no FDA coverup. No bombshell.

Just anti-vaccine folks continuing to try and scare you away from vaccinating and protecting your kids.

More on the Licensing of the MMR Vaccine

Making a Better Pertussis Vaccine

So we know that we need a better pertussis vaccine.

DTaP and Tdap just aren’t doing the job that they should be doing.

Whooping Cough is back, again.
Whooping Cough is back, again.

So when will we get one?

Making a Better Pertussis Vaccine

Since anti-vaccine folks are always talking about the 300 new vaccines in the pipeline, you would think that we would have had several new pertussis vaccines by now…

Unfortunately, we don’t.

What we do have is some good candidates, including:

  • new acellular pertussis vaccines, either with more antigens or an adjuvant
  • a new live attenuated nasal vaccine, BPZE1
  • new whole-cell vaccines with reduced endotoxin contents (so should have fewer side effects that then original whole-cell pertussis vaccine – DTP)

Before you get too excited, keep in mind that none of these vaccines will be available in your pediatrician’s office any time soon. Developing a new vaccine takes a lot of time.

BPZE1 has started phase 2a trials though.

What do we do until we get new pertussis vaccines?

“We should be more vigilant than we have been in the past to recognize and treat pertussis in all age groups so that transmission to young infants is reduced. Most important (although not discussed in this review) is to ensure that all pregnant women receive the Tdap vaccine between 27 and 36 weeks’ gestation with each pregnancy. Also, we should consider routinely administering Tdap vaccine every 3 years to all adolescents and adults who were primed with a DTaP vaccine.”

James D. Cherry on The 112-Year Odyssey of Pertussis and Pertussis Vaccines—Mistakes Made and Implications for the Future

We should keep using the pertussis vaccines we have!

Vaccines work, even when they aren’t as effective as we would like.

More on Making a Better Pertussis Vaccine

Where are the Saline Placebos?

Remember when anti-vaccine folks used to say that there were no double-blind, placebo-controlled randomized clinical trials for vaccines?

What happened once they realized that there actually were?

They moved the goal posts…

Where are the Saline Placebos?

Okay, they said.

So you have done double-blind, placebo-controlled randomized clinical trials when testing vaccines, but what placebo did you use?

Was it a pure saline placebo?

“Placebo Control – A comparator in a vaccine trial that does not include the antigen under study. In studies of monovalent vaccines this may be an inert placebo (e.g. saline solution or the vehicle of the vaccine), or an antigenically different vaccine. In combined vaccines, this may be a control arm in which the component of the vaccine being studied is lacking.”

WHO on the Guidelines on clinical evaluation of vaccines: regulatory expectations

Although no guidelines actually call for using a pure saline placebo, that’s all anti-vaccine folks will accept these days.

Why?

That’s there MO – or method of operation.

When one theory or myth gets squashed – they move to another.

They move the goalposts.

It doesn’t matter that there are often ethical and logistical problems with using pure saline placebos, that’s all they want to hear about it.

That they wouldn’t be satisfied and start vaccinating their kids if all vaccine studies started to use saline placebos should be evident when you consider that many vaccine studies have already used saline placebos!

There are many more vaccine studies that have used saline placebos and like other vaccine studies, have found vaccines to be safe and effective.

But how do you know that they used a real saline placebo and not some kind of saline solution with other stuff in it?

If it isn’t clear to you in the methods section of the study, go to the source – the original clinical trials record and it will be listed there.

What are you going to be worried about now?

More on Saline Placebos

Why Aren’t Vaccines Regulated like Drugs?

Have you ever heard the argument that vaccines aren’t held to the same standards as drugs, food, or other products?

“Vaccines are not held to the same double blind gold standard of clinical testing as other pharmaceutical drugs because they are considered biological products under the Public Health Federal Food, Drug and Cosmetic Act. They meet the same standards as cosmetics.”

20 VACCINE “FACTS” you need to know to make an informed decision

Placebos, liability, testing – these are all arguments that anti-vaccine folks try to use to scare parents into thinking that vaccine development isn’t well regulated and vaccines aren’t held to the same standard as drugs.

Why Aren’t Vaccines Regulated like Drugs?

Would you be surprised to learn that part of their argument is true?

Even after approval by the FDA, a vaccine still has to be reviewed by the ACIP before it is put on the immunization schedule.
Even after approval by the FDA, a vaccine still has to be reviewed by the ACIP before it is put on the immunization schedule.

No, not the part that vaccine development isn’t well regulated!

“Current authority for the regulation of vaccines resides primarily in Section 351 of the Public Health Service Act and specific sections of the Federal Food, Drug and Cosmetic Act.”

Vaccine Product Approval Process

Federal regulations and rules ensure that our vaccines are safe.

  • Public Health Service Act (42 USC 262-63) §351
  • Food, Drug, and Cosmetic Act (21 USC 301-392)
  • Title 21 Code of Federal Regulations (CFR) 600-680 – standards for biological products
  • Title 21 CFR 314 (21 CFR 601.25[d][2], specific to biologicals – ensures adequate and well-controlled clinical trials
  • Title 21 CFR 312 – investigational new drug application (IND)
  • Title 21 CFR 210-211 – good manufacturing practices
  • Title 21 CFR 58 – good laboratory practices
  • Title 21 CFR 56 – institutional review boards
  • Title 21 CFR 50 – protection of human subjects
  • Prescription Drug User Fee Act (PDUFA) of 1992, 2002, and 2007
  • Food and Drug Agency Modernization Act (FDAMA) of 1997
  • Food and Drug Agency Amendments Act (FDAAA) of 2007

I meant the part that vaccines aren’t regulated like drugs.

While both vaccines and prescription drugs are regulated by the FDA, that work occurs within two different centers of the FDA:

  • Center for Biologics Evaluation and Research (CBER) – vaccines
  • Center for Drug Evaluation and Research (CDER) – over-the-counter and prescription drugs

Both centers work to make sure we have safe and effective vaccines and drugs to keep us healthy, even if there are some differences in how they do it.

“Vaccine clinical development follows the same general pathway as for drugs and other biologics.”

Vaccine Product Approval Process

That’s right, vaccines and drugs go through the same types of clinical trials.

After completing the three phases though, vaccine developers must then apply for a Biologics License Application (BLA), which is reviewed by a multidisciplinary FDA reviewer team. This is also when their manufacturing facility gets inspected.

“Following FDA’s review of a license application for a new indication, the sponsor and the FDA may present their findings to FDA’s Vaccines and Related Biological Products Advisory Committee (VRBPAC). This non-FDA expert committee (scientists, physicians, biostatisticians, and a consumer representative) provides advice to the Agency regarding the safety and efficacy of the vaccine for the proposed indication.”

Vaccine Product Approval Process

Once approved and licensed, the FDA and CDC continue to work to make sure the vaccine is safe, including having some vaccines undergo undergo Phase 4 studies and monitoring for side effects through VAERS and the Vaccine Safety Datalink.

And then, even after approval by the FDA, new vaccines aren’t put on the immunization schedule until a review and approval by the Advisory Committee on Immunization Practices (ACIP).

“Canada, like many other countries, exercises tight regulatory oversight over vaccines because they are usually given to very large numbers of healthy individuals. Vaccines in Canada are subject to the Food and Drugs Act and the Food and Drug Regulations. Vaccines are regulated under a specific set of regulations for a subset of drugs known as biologic drugs.”

The Regulation of Vaccines for Human Use in Canada

It is also important to keep in mind that this process doesn’t just happen in the United States.

Still wondering why vaccines aren’t regulated like drugs?

“Vaccine development differs from drug development in several important ways. First, because vaccines are preventive and are given to healthy individuals – often children – they require very large clinical trials, leading to increased research and development costs. Second, vaccines are biological products that can be very complex to manufacture and are subject to stringent quality control standards, resulting in much higher capital costs. Third, unlike drugs, vaccines have no secondary markets, making it unlikely that manufacturers will generate additional profits beyond the initial target markets. Finally, unlike generic drugs, which only need to demonstrate adherence to a pre-established development process, vaccines are biologicals that require full re-development to demonstrate their equivalence. (World Health Organization, 2014). Each manufacturer is required to invest in the full regulatory approval process for their vaccine products.

Myths and Facts about Vaccine Product Price and Procurement

It’s only because vaccines are more strictly regulated than drugs and other products.

Vaccines are safe and necessary.

More on Vaccine Regulation

Et Tu, Slate? Flaws with Their Questions About Gardasil

Questioning vaccines doesn’t make someone anti-vaccine.

Something is missing in this article about Gardasil testing in Slate...
Something is missing in this article about Gardasil testing in Slate…

Doing a poor job of it and making folks scared to get vaccinated and protected?

I’ll let you decide what to call them…

Slate Investigates the Gardasil Clinical Trials

So after an eight-month long investigation, a journalist for Slate thinks he has evidence that the clinical trials that helped get Gardasil approved by the European Medical Agency were flawed.

What was the problem?

The way that they recorded possible side effects after folks were vaccinated.

“To track the safety of its product, the drugmaker used a convoluted method that made objective evaluation and reporting of potential side effects impossible during all but a few weeks of its years long trials.”

What made the method convoluted?

“In an internal 2014 EMA report about Gardasil 9 obtained through a freedom-of-information request, senior experts called the company’s approach “unconventional and suboptimal” and said it left some “uncertainty” about the safety results.

Merck, which is known as Merck Sharp & Dohme outside the U.S. and Canada, did not address the EMA’s safety concerns.”

When you read the internal 2014 EMA report about Gardasil 9, it is clear that Merck has a thorough response to each and every question that the EMA asked.

And those other quotes?

The EMA does state that:

  • “At all other time points in the study medical events were reported as “new medical history”. This is an unconventional and suboptimal study procedure.”
  • “While it is considered that the required safety data eventually has been made available for assessment, this feature of the study protocol brings some degree of uncertainty into safety assessment.”

So the EMA got the required safety data they were looking for, which is likely why Gardasil was approved in Europe.

They also said that “As the AE reporting procedure as seen at the inspection sites was in line with the approved protocol, the inspectors did not comment on it in the inspection reports. It was discussed with assessors during the course of the inspections, as in the inspectors’ opinion it is not an optimal method of collecting safety data, especially not systemic side effects that could appear long after the vaccinations were given.”

This case of a subject with POTS was reported as being "well characterized" by the EMA, even though it likely wasn't caused by her Gardasil shots.
This case of a subject with POTS was reported as being “well characterized” by the EMA, even though it likely wasn’t caused by her Gardasil shots.

But if it was suboptimal, how come they were able to record someone getting diagnosed with POTS 1,389 days after their third dose of vaccine?

I’m starting to understand why Dr. Yehuda Shoenfeld wasn’t quoted in the piece. He likely knew how it was going to be perceived…

“Imagining a link between HPV vaccination and CFS is not all that far-fetched, according to Dr. Jose Montoya, a professor of medicine at Stanford University and a CFS expert.”

Not far-fetched at all, which is why studies are done to see if there really is a link.

So even if part of the study design was suboptimal, the Slate piece shouldn’t have cherry picked those quotes and should have included these other big pieces of information:

  • A study in the UK using the MHRA’s Yellow Card passive surveillance scheme found no increase in reports of chronic fatigue syndromes following the introduction of Cervarix (another HPV vaccine)
  • In 2015, the EMA confirmed evidence that HPV vaccines do not cause complex regional pain syndrome (CRPS) and postural orthostatic tachycardia syndrome (POTS)
  • A large, nationwide register-based study from Norway found no indication of increased risk of chronic fatigue syndrome/myalgic encephalomyelitis following HPV vaccination
  • A large cohort study of over 2 million young girls in France found no risk for autoimmune diseases (including neurological, rheumatological, hematological, endocrine, and gastro-intestinal disorders)
  • A large cohort study of girls in Sweden with pre-existing autoimmune diseases found that HPV vaccination was not associated with increased incidence of new-onset autoimmune disease (49 types of autoimmune diseases)
  • A review of VAERS reports that “did not detect any unusual or unexpected reporting patterns that would suggest a safety problem” with HPV vaccination

The Slate piece does mention two of these studies, but just barely. One gets a single sentence and the other, half a sentence.

We see page after page of anecdotes of folks with supposed vaccine injuries, but the evidence that shows the vaccine is safe is almost buried and easy to miss. Many of the other studies seem to be left out.

And just because these patients have agonistic auto-antibodies, it doesn’t mean that they are from a vaccine.

“Five of the 14 POTS subjects and 2 of the 10 “healthy controls” recalled a respiratory infection in the 6 months prior to onset of their symptoms or inclusion in the study for the healthy controls.”

Li et al on Autoimmune Basis for Postural Tachycardia Syndrome

Lastly, what’s with calling cervical cancer uncommon???

“Cervical cancer is the 4th most common cause of cancer death in women worldwide, with tens of thousands of deaths in Europe each year despite the existence of screening programmes to identify the cancer early.”

European Medicines Agency

Downplaying the risks of vaccine-preventable diseases, while trying to scare folks about vaccines – that’s what gets you labeled as anti-vaccine.

The HPV vaccines are safe. They work and they are necessary. Don’t skip them.

What to Know About the Slate Gardasil Investigation

Although the study design for Gardasil used for licensing in Europe might have been suboptimal, that doesn’t really come across in this Slate piece, as it seems clear that it didn’t result in safety data being missed, and as post-licensure tests have confirmed, Gardasil is safe.

More on the Slate Gardasil Investigation

Are Vaccines Evaluated for Mutagenicity, Carcinogenicity or Impairment of Fertility?

Spend much time on anti-vaccine websites or forums and you will soon be warned that vaccines are not evaluated for mutagenicity, carcinogenicity or impairment of fertility.

Actually, you can often read that simply by reading a vaccine’s package insert.

Mutagenicity, Carcinogenicity and Impairment of Fertility

What are these term exactly?

  • mutagenicity – being known or suspected of causing mutations in our DNA, which can lead to cancer
  • carcinogenicity – being known or suspected of being able to cause cancer
  • impairment of fertility

And why are they listed in Section 13 of a vaccine’s package insert?

The Section 13 Vaccine Conspiracy?

More importantly, why do some folks talk about Section 13.1 of a vaccine’s package insert like it is Area 51 or Agenda 21?

“13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, mutagenesis, impairment of fertility. This subsection must state whether long term studies in animals have been performed to evaluate carcinogenic potential and, if so, the species and results. If results from reproduction studies or other data in animals raise concern about mutagenesis or impairment of fertility in either males or females, this must be described. Any precautionary statement on these topics must include practical, relevant advice to the prescriber on the significance of these animal findings. Human data suggesting that the drug may be carcinogenic or mutagenic, or suggesting that it impairs fertility, as described in the “Warnings and Precautions” section, must not be included in this subsection of the labeling.”

CFR – Code of Federal Regulations Title 21

So no material for a vaccine conspiracy?

Just information on studies in animals?

“The goals of the nonclinical safety evaluation generally include a characterization of toxic effects with respect to target organs, dose dependence, relationship to exposure, and, when appropriate, potential reversibility. This information is used to estimate an initial safe starting dose and dose range for the human trials and to identify parameters for clinical monitoring for potential adverse effects. The nonclinical safety studies, although usually limited at the beginning of clinical development, should be adequate to characterize potential adverse effects that might occur under the conditions of the clinical trial to be supported.”

FDA on Guidance for Industry M3(R2) Nonclinical Safety Studies for the Conduct of Human Clinical Trials and Marketing Authorization for Pharmaceuticals 

It still sounds important though…

Are Vaccines Evaluated for Mutagenicity, Carcinogenicity or Impairment of Fertility?

As important as vaccines are, no one wants them to mutate our children, cause cancer, or keep them from having babies.

Fortunately, they don’t!

“To ensure the safety of new vaccines, preclinical toxicology studies are conducted prior to the initiation of, and concurrently with, clinical studies. There are five different types of preclinical toxicology study in the evaluation of vaccine safety: single and/or repeat dose, reproductive and developmental, mutagenicity, carcinogenicity, and safety pharmacology. If any adverse effects are observed in the course of these studies, they should be fully evaluated and a final safety decision made accordingly. ”

M.D. Green on the Preclinical Toxicology of Vaccines

And that’s because vaccines are safe and well tested.

Then why do anti-vaccine folks scare parents into thinking that vaccines are missing necessary testing when the package insert states that they are “not evaluated for mutagenicity, carcinogenicity or impairment of fertility?”

Cancer is caused by a host of factors. Vaccines have a role in preventing and potentially treating some types of cancer. Components of vaccines and their associated cell lines that viruses are grown in are safe and have not been shown to induce cancer in the vaccinated host.
“Cancer is caused by a host of factors. Vaccines have a role in preventing and potentially treating some types of cancer. Components of vaccines and their associated cell lines that viruses are grown in are safe and have not been shown to induce cancer in the vaccinated host.”

Probably because it sounds scarier than saying that vaccines have a low risk of inducing tumors and that there are very specific guidelines and rules for when a manufacturer needs to perform fertility studies.

That means that if  a package insert says that it has “not been evaluated,” it is simply because it was not necessary or appropriate. It is not because they just didn’t want to do it and left those tests out.

That doesn’t sound as scary though.

All necessary pre-clinical or nonclinical testing is done on vaccines and their components. You just don’t see long term testing that would be listed in the package insert unless the initial tests found a problem.

Also remember that vaccines are monitored through several passive and active safety systems that would detect issues with mutagenicity, carcinogenicity, and impairment of fertility.

And several vaccines actually prevent cancer!

What to Know About Vaccines and Mutagenicity, Carcinogenicity and Impairment of Fertility

Vaccines are appropriately evaluated for mutagenicity, carcinogenicity and impairment of fertility, when necessary, as a part of pre-clinical or nonclinical studies that occur even before the first phase one studies on people.

More About Vaccines and Mutagenicity, Carcinogenicity and Impairment of Fertility

 

Is the HPV Vaccine a Savior or the Most Dangerous Vaccine Ever Made?

I’m still surprised at the responses some parents have when I mention that it is time for their kids to get their HPV vaccine.

Despite what you might read on the Internet, the HPV vaccines are safe and necessary.
Despite what you might read on the Internet, the HPV vaccines are safe and necessary.

While most say things like, “good, I was wondering when they would start it,” a minority still use arguments that could come straight off of any anti-vaccine website or forum.

Is the HPV Vaccine Dangerous?

The HPV isn’t dangerous, but it is easy to see why some parents still think that it is.

How many myths about the HPV vaccine have you heard?

“I don’t like this vaccine… Heaven help us if we have a generation of kids who get a hepatitis B vaccine and a HPV vaccine and they think that now unprotected sex is okay…

I don’t think it is really clear that this vaccine is really as safe as they say it is and it is certainly not as dangerous as they say it is, but I recommend against it in my practice.”

Dr. Jay Gordon discussing the HPV vaccine on the Ricki Lake Show

You can rest assured that they aren’t true.

Deciding to Get an HPV Vaccine

The HPV vaccines are well studied and in continuing studies have only been found to cause mild side effects, just like most other vaccines.

Still undecided?

“The manufacturers of Cervarix and Gardasil are following patients in Scandinavia for at least 15 years to verify that protection from both vaccines lasts at least that long.”

National Cancer Institute on HPV Vaccines

Parents who are still hesitant should know that:

  • Gardasil, the first HPV vaccine, was approved by the FDA in 2006. The first phase 1 and phase 2 trials began in 1997. It has been given to over 200,000,000 children, teens, and young adults for over 10 years now all over the world.
  • while fainting might occur after vaccination, it is also not uncommon after other vaccinations and medical procedures, especially in teens. It is not a specific issue caused by the HPV vaccine or any vaccine, for that matter.
  • the HPV vaccine does not cause primary ovarian failure, venous blood clots, behavior problems, multiple sclerosis, autoimmune disorders, or any of the other serious side effects you read on the Internet
  • while the HPV vaccine won’t protect against all forms of HPV, it protects against the forms that are most likely to cause cervical cancer. Just two types of HPV, types 16 and 18, cause 70% of cervical cancers, and another two types, types 6 and 11, cause 90% of genital warts. All are included in the Gardasil vaccine and Cervarix includes the types most likely to cause cervical cancer.
  • HPV is not rare – in fact, it is the most common sexually transmitted infection in the United States. While many infections do go away on their own, spontaneously, others linger and can cause cervical cancer.
  • HPV doesn’t just cause cervical cancer though, it can also cause vaginal, vulvar, penile, and anal, and oropharyngeal cancer, and genital warts
  • the HPV vaccines seem to provide long lasting protection, although, as with any new vaccine, we won’t know just how long the true duration of protection is until the vaccines have been out even longer. So far, Gardasil and Cervarix are providing protection that lasts at least 8 and 9 years.
  • boys need the HPV vaccine too, as there are around 11,000 cases of HPV induced cancer in men each year, including anal cancer and cancers of the mouth/throat and penis.
  • you want your child to get the HPV vaccine before they are having sex, to prevent them from ever getting infected with HPV, which is why it is routinely recommended when kids are 11 to 12 years old. That they are not sexually active yet is the whole point! As with other vaccines, if you continue to wait, you might eventually wait too long, although you can still get the vaccine if they are already sexually active, even if they are already infected with HPV, as it might protect them against another strain that they don’t have yet.
  • getting the HPV vaccine does not make it more likely that a teen will have sex
  • using condoms will not prevent all HPV infections. HPV can also spread through nonpenetrative sexual contact.
  • cervical cancer is serious, with about 4,200 women dying of cervical cancer each year, even in this age of routine pap tests
  • although you may hear that the HPV vaccine has been banned in some places, it is still offered in Japan, Utah, and other places where they talk about these bans, and since 2014, at least 64 countries have added the HPV vaccine to their immunization schedule

Get educated about vaccines and get your kids their HPV vaccine series. Remember that if you start the series before your kids are 15 years old, they only need two doses of the vaccine. After 15 years, they need 3 doses.

What To Know About Deciding to Get an HPV Vaccine

The HPV vaccines are safe, they work, and are necessary, which are beliefs shared by experts and most parents who decide to get their kids vaccinated and protected against HPV.

More Information on Deciding to Get an HPV Vaccine

 

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