It’s taken me a little while to put virtual pen to paper in response to the appalling report from Reuters that revealed how an official US-government-sanctioned campaign set out to deliberately undermine COVID vaccination efforts in the Philippines.
Through phony internet accounts meant to impersonate Filipinos, the military’s propaganda efforts morphed into an anti-vax campaign. Social media posts decried the quality of face masks, test kits and the first vaccine that would become available in the Philippines – China’s Sinovac inoculation.
Reuters
The program, which apparently ran from 2020 through the end of the Trump administration and months into 2021, was a deliberate act of propaganda to undermine the influence of China on the global COVID vaccine stage (which the USA was not contributing to at all at the time). While Americans were “not targeted” by the misinformation, that specifically set out to disparage and undermine the Sinovac vaccine that was in widespread use in that region at the time, there cannot be any doubt that the lives of locals were placed at risk. As an infectious disease specialist who has dealt with antivaccine misinformation for all of their professional career, this is simply unacceptable to me. Regardless of the relative merits of one vaccine over another, or the petty machinations of the political regimes, during a global pandemic it is an abject failure of humanity to deliberately place other human beings in harm’s way.
This isn’t the first time that vaccines have been used as tactical tools – in the hunt for Bin Laden the CIA used a hepatitis vaccine program to collect DNA from children in an attempt to discover links to the terrorist in hiding. When the ruse became public, vaccine workers (even those with nothing to do with the program) were targeted and the polio eradication campaign stalled, with effects that have taken over a decade to even start to undo.
In response to the Pentagon’s efforts to undermine China, Filipino vaccine rates were woefully low, to the extent that the Government had to threaten jail for those who refused vaccination. When the US was approaching herd immunity at 65% coverage, in June 2021 the Philippines had only about 2% of their population immunized.
It takes a special kind of heartless disregard for science, and the welfare of other human beings, to promote this kind of act and go along with it. I suppose should we expect anything less, coming from a political leader who downplayed the seriousness and very existence of the problem and then politicized masking and social distancing, even as they sent protective equipment to their political allies. After vaccines became widely available, the anti-science mindset among Republicans was responsible for a 43% higher rate of excess deaths compared to Democrats in Florida and Ohio.
Arguably, deliberately undermining vaccine programs for political gain is tantamount to poisoning a water supply, which is literally a war crime. I cannot overstate how upset I am about this entire story – we as the experts have a hard enough time educating a scared and skeptical public about the measures that we are recommending to literally save them from themselves, without having our work attacked and undone by the powers that be.
A recent headline caught my eye, discussing an increase in the annual reported cases of Powassan virus – a virus which (for reasons that will become obvious) is near and dear to me. I decided to take a look at the actual data in more detail, and discuss a bit of that here, because understanding viruses like Powassan has implications beyond just this one infection.
Let’s start with what Powassan virus really is – it’s an arbovirus, meaning transmitted by arthropods (in this case, Ixodes ticks), and has an ability to cause a form of encephalitis. It is in fact closely related to the Tick Borne Encephalitis (TBE) virus, but Powassan virus was actually named after the town in Ontario where it was first discovered. It’s highly likely that many (perhaps the majority) of infections don’t go on to cause very serious disease, but the actual risk of encephalitis from it is unknown because the total number of cases isn’t really known. Of the symptomatic cases, about half are quite serious and 10% are fatal. The CDC has made it a nationally reportable infection, but the tricky part is knowing when to even think about it…
I diagnosed the first ever case of Powassan in Connecticut in 2016. It really was a bit of a crazy story, and truly a perfect storm of being in the right place at the right time. A young infant boy was admitted to the ICU with seizures and a very clear story of a few hours of a tick being attached to his leg 2 weeks earlier. The tick was brought into the house on a family member’s clothing, and probably got onto the child during a feed while being held by this person. The medical team had quite correctly ruled out most tick-borne infections due to the very short attachment time, but I knew that there was one exception – at least in animal models, Powassan virus could be transmitted in as few as 15 minutes. So it was possible, but was it probable? The clincher was the MRI report, which had a very distinct pattern showing “restricted diffusion of the basal ganglia and rostral thalami, as well as the left pulvinar”. There was no sign of more widespread of diffuse signal changes as you might see with ADEM (acute disseminated encephalomyelitis) or cerebellar changes as you might see with enterovirus. No hemorrhagic changes, as with herpes simplex. The laterality and location of the damage matched the physical symptoms (motor dysfunction affecting the right more than left), but more importantly it was also similar to previous reported scans from patients with arthropod-borne flaviviruses, including Powassan. Choi and Taylor wrote in a 2012 case report “MRI images of the patient’s central nervous system (CNS) were unique, and when such images are encountered in the clinical setting, Powassan viral infection should be considered.” We were able to test the baby’s spinal fluid at the CDC for Powassan, and it came back positive.
The points to make about this case are several – firstly, the recurring comment from most (probably all) of my colleagues when I made the diagnosis was “What made you think of it?” Honestly, it was mostly the fact that I had training in a state where Powassan was well-known and we would consider it routinely. I simply added it to the differential and saw that not only could I not rule it out, I had some evidence to support it! But the issue here is that there were probably many cases of Powassan over the years that doctors had been seeing, but simply never thought of testing. Powassan was not on a routine viral encephalitis panel in Connecticut (it’s a send-out to the CDC), whereas some other State laboratories like New York test for it automatically on their own encephalitis panel, in addition to sending/reporting to the CDC. It is very much a case of out of sight, out of mind.
Secondly, even if some physicians had considered and tested for the virus somehow, Connecticut didn’t make Powassan a reportable disease until 2019 (more than 2 years after I made the first diagnosis in the state). It’s really hard to measure something if you’re not counting it…and of course even hard to count something if you’re not looking for it!
So this makes it really, really hard to know what to do with news that “Powassan cases are increasing.” Reports are increasing, but so is awareness, and testing availability – it doesn’t mean that actual infections with the virus are going up. It is possible that they are…but the case reports alone aren’t enough to make that conclusion. You really have to understand the reporting infrastructure and testing limitations in the context of a specific disease when trying to interpret the changes you might see in any sort of incidence or prevalence data.
There isn’t a vaccine yet for Powassan virus, although when I last checked research was ongoing (and there is a vaccine for TBE). The best way to prevent infection is to avoid any kind of tick exposure at all – cover skin, use DEET, avoid tramping through the wilderness in areas where the virus is known to be in ticks, and check your pets! Also – change your clothing when you get indoors from activities that might have exposed you to ticks…
Bonus if you’ve made it this far – you can check out my TV appearance on Monsters Inside Me below!
I heard a little more recently on the contaminated blood scandal of the 1980s, where huge numbers of people with hemophilia were given treatments for their condition that were contaminated with viruses, including HIV and Hepatitis C.
Early on, there was little knowledge about the true risks of these viruses, and no proper testing available (certainly not widely available), but it turns out that some of this story is even worse than simply being given contaminated blood products.
An inquiry in the UK is currently focused on a specific series of infections that occurred at one particular school, which had a hemophilia treatment center on-site and which, it turned out, was also conducting research into novel treatments for the disease. At a superficial level the research seemed sound – it was asking the question: would a new heat-treated version of the clotting factors needed to treat hemophilia be safer than the standard treatments? Unfortunately, the heat-treatment wasn’t sufficient to completely inactivate the viruses – but the story is much worse than just that.
Several people have come forward who not only were infected with the viruses anyway, but possibly didn’t need treatment for their hemophilia at the time they were given the experimental treatments and, worse, neither they nor their parents were properly consented for the research. When the true risks of infection were obvious, subjects weren’t told, and some weren’t even informed of their infections for a year or more. One doctor involved in the study, a Dr Samual Machin (now deceased) is quoted during the inquiry:
“This would have been discussed with his mother, although I acknowledge that standards of consent in the 1980’s was quite different to what it is now,”
At the time, the subjects were all children, and several of the parents denied being properly told about the research, and that they would not have consented had they been told. Further documents showed that untreated patients were highly sought after, and that trying out the new heat-treated therapy may have been prioritized over the patients actual medical needs.
There are several core principles of research at stake here – beneficence (doing good), non-maleficence (do not do anything bad) and autonomy (being able to make your own decisions). Even a cursory look over the stories of this case show that none of those principles were upheld in this research, and of course the fact that the heat-treatment didn’t work to inactivate the viruses makes it all the worse (arguably if the research was a stunning success there wouldn’t be an inquiry into any of this…but that’s a whole other topic for discussion).
While there are regulatory rules for ensuring proper scientific conduct of research, there are also ethical rules. The two have some overlap, but they really are distinct frameworks, within which researchers have to function. The sad fact is that many of the rules and protections that we now take for granted were imposed as a direct consequence of past unethical human experimentation (which leads to another discussion about how what is considered “ethical” changes over time). From the perspective of human subjects and safety in particular, these are reflected primarily in the document we know as the ICF – the Informed Consent Form.
While it’s true that many aspects of subject safety, rights, and welfare are contained within the research protocol, the protocol itself is a highly technical description of the research and as more of a scientific justification and research plan. The ICF on the other hand is intended to be seen and understood by the study subject themselves, and includes a discussion on the research protocol (visits, procedures, timeline, risks etc.) in addition to making them aware of certain other rights afforded to them, including the right to leave the study at any time and any other treatment options available. The research site’s institutional review board (IRB) would have reviewed and edited the ICF to ensure that it accurately reflected the research risks and benefits prior to being seen by a potential subject. IRBs include subject-matter experts as well as members of the lay public to ensure clarity and understanding. Not only are potential study participants supposed to be given the opportunity to ask questions before signing the ICF, but they receive a copy and a copy remains in their medical record.
The fact that no such process occurred in these contaminated blood product studies is obvious.
Unfortunately, stories like this from research done decades ago, and which clearly doesn’t meet current standards, color everybody’s opinion of medical research. I have had parents refuse to consent for a study because “The sponsor is [insert drug company with research scandal] and I don’t trust them,” even though the drug in the study had nothing to do with the risks from the older scandal. I heard about one parent who turned down a study because of a poorly written ICF, that ironically overstated the risks in a summary paragraph that implied the drug had never been given to anyone before – some people might have continued reading, but this parent did not (they did however provide that feedback to the investigator, so we were able to modify the ICF to make it more clear). One time I had a sponsor try to avoid explaining all the risks (for the control therapy, not the study drug) in the ICF and instead provide a patient hand-out or “your doctor will explain this to you” verbiage. Despite our warning that the IRB would reject this ICF, they insisted on submitting it and of course wasted a whole IRB review cycle as they were forced to revise and resubmit the document with our recommended wording. This wasn’t an intentional thought to mislead, they genuinely thought it was a more efficient process and would avoid scaring the subject unnecessarily, but we knew that the ICF should be a stand-alone record of the subject being truly informed before consenting.
One of my experiences with obtaining consent sticks out to me – it was a slowly-recruiting antibiotic study and I was hoping to not have another screen-failure at my site. I had found a possible subject and was discussing the study with his mother and my study nurse. The mother was asking careful questions, clearly a little nervous (her son was in hospital after all!) and I was thinking that she probably wasn’t going to sign him up when she suddenly said “You know what, you’re the doctor and you know best, I’ll do whatever you say.” Massive red flag to me, as an investigator. Research isn’t the same as medical care – if “I knew what was best” we wouldn’t be having a conversation about a clinical trial! Also, if something were to happen during the study and she had rescinded the decision to me, then she as a mother would feel far worse than if she had made the decision truly believing she had made the best call. So I called “Investigator fiat” and screen-failed them. Every set of inclusion/exclusion criteria includes a line about “any other condition which, in the opinion of the Investigator. would interfere with the conduct of the study” and at that point I’m not sure that she fully understands the risks and benefits.
While we might celebrate some of these stories as holding ourselves to a high standard, the sad truth is the current standards of oversight and training that we have in medical research are much better than they were in the past mostly because of how poor they were in the past. Personally, I find it shocking that some of this occurred within my lifetime, and I think it behooves us to be mindful every day about how we conduct our research, placing the rights and welfare of our participants first.
In my ongoing saga series on clinical research, I thought I’d share my thoughts on the advantages and disadvantages of requiring regional medical monitors be located in specific countries.
One of the points raised during the planning stages of a clinical trial is often the geographic location of the team members. The Clinical team in particular pretty much has to be based locally because they will be performing site visits and interacting very closely with the staff and investigators, but it’s not unusual for other team members to be based around the globe. Data management team members for example are frequently located in Asia due to a large population of skilled talent available at more economic salaries than if they were based in Western Europe or the USA, and the fact that their work can readily be performed remotely and asynchronously with the rest of the project. But what about the Medical team?
The Medical Monitors are typically physicians with at least some experience in clinical practice (although the actual time people have spent varies considerably), and many have some degree of subspecialty training. The interesting thing is that a very large part of the job is subspeciality agnostic – the safety data we review all looks the same, and it’s largely a case of lining up the findings with the study-specific protocol to weed out the more detailed anomalies. Whether the study drug is being given for one thing or another is largely a moot point. When looking at things like protocol design and study planning and execution, there is absolutely an element of subspeciality knowledge required, but it isn’t that unusual for a physician trained in one area to find themselves working on a clinical trial in another. Furthermore, clinical trials are often global in nature and may have sites not just in different time-zones, but on different continents, and the Medical Monitoring work itself is readily performed remotely. For this and other reasons, the physical location of the Medical Monitor may not be considered relevant, but I would argue that there are very good reasons to keep the Medical team regional and optimized for the study, beyond the simple consideration of time-zones.
In the early planning stages, similar to being a subject matter expert from the disease/treatment perspective, it can be critical to have the insight of a local physician when considering things like screening failure rates, ease of enrollment, site and investigator selection, and even country-specific nuances on treatment guidelines or standards of care. For example, if a protocol requires that a specific comparator drug be used, but that drug isn’t approved or recommended in some countries, then it would be a mistake to try to conduct the study in those countries. Certain medical conditions are more or less common around the world, whether due to genetic or environmental factors, and these can dramatically impact enrollment rates and timelines. While it is true that a lot of this information can be obtained and understood by any physician, I think it’s still prudent to consult someone with that knowledge from a medical perspective.
During one large project I was on, we received feedback that a particular medical test was likely under-budgeted, which might lead to sites refusing the take the study on if it were not reimbursed properly. It was something that was highly unusual in routine medical care, but which I happened to have knowledge of and an awareness of the complexity of the procedure. Having an awareness also of the way the American healthcare system tracked and billed for these tests, I was able to direct the budget analysts to the correct amount to cover which impacted not just the proposal I was currently working on, but any others that used the same test. Someone without that knowledge of how the system worked might not have even known that there was an answer out there to find, never mind find it.
One area that is also important, although it’s often not realized until it’s needed, is clear communication with the sites and Investigators. While it’s true that English is widely used and understood, and tends to be the “lingua franca” of the research world, it’s also true that English is a second language for most. It seems prudent, if not simply polite, to be able to converse with site staff and investigators in their native language, and furthermore to have the social cues and etiquette familiar to them. I can speak French fairly well, but I know I cannot communicate the nuances in French that I can in English. At best, this can slow down communication if a third-party is required on a phone call to interpret in real time – at worst, it can lead to miscommunication and inadvertent offense. I have found that the issues are compounded if a person who natively speaks one language converses in English with someone who natively speaks another, and because clarity and attention to detail are SO important, I think it does behoove us to consider this aspect of study execution when assigning Medical Monitors. I don’t think this necessarily requires physicians geographically local to the sites, but doing so definitely decreases the odds of miscommunication.
Having already said that geographic location is irrelevant when considering the basic data and safety review tasks (with the exception of nuances in country/region specific regulatory reporting of urgent cases), there is other reasons for appointing Medical Monitors in alternative locations to the main study sites, especially if the time-zones at least line up. For one, it may be economically advantageous to hire on physicians from certain countries, or the volume of work may simply require multiple people with the team members scattered. There is also the very real possibility that the most experienced or suitable physician for that study isn’t local, or the sponsor may have a specific preference based on past experience with that person, so obviously a number of factors need to be considered.
Importantly, because the needs are different for project development versus execution, It may be the case that the subject-matter expert assigned to the initial proposal team isn’t assigned as the Medical Monitor. In that situation, it’s crucial for a comprehensive hand-off/kick-off meeting to occur to make sure that any issues or risks identified during the initial work are communicated over to the main team.
From the perspective of the sponsor, I would consider all of these issues when looking at the Medical Monitor assigned to your study – what aspects are most important to you, and what tasks are they most likely to be performing? I would say that if site communication and insights are important, then advocating for a local assignment would be a good idea. If you consider that subject-matter or clinical trial design expertise is more important, then you may want to be targeted in your selection regardless of geographic location. I am also a huge advocate for remote working for Medical Monitors, especially when considering all the factors above: there is a finite pool of experienced experts and if you happen to find someone with the right mix of clinical and research time, covering the right subject-matter, and with the personality and work-ethic to excel in clinical research, you absolutely should not limit your recruitment to physicians who are willing to relocate. Most physicians who are at the stage in their careers where a move to industry is feasible are in their middle years, settled with children and houses, and in many cases burned out with the time and demands of clinical care. Being told they have to uproot their family and commute through traffic to a desk job in an office is not appealing at all. I have seen several companies, both in the CRO world and in big Pharma (less so in Biotech interestingly enough), require their Medical Monitors to relocate and work on-site. I simply do not think there is a need for that in this line of work, especially in the post-pandemic era where work-from-home infrastructure is so well developed. If you’re requiring your talent to relocate you’re effectively giving the talent away to your competitors…
What’s been your experiences working as, or with, a regional medical monitor? I’d love to hear about the advantages and challenges you’ve experienced.
In my first post on Clinical Research, I mentioned how important it was for Investigators to adhere to the protocol, but I didn’t really go into detail on the whys and wherefores. Protocol Deviations (PDs) are often misunderstood, even by those who are tasked with identifying and categorizing them, so I wanted to write this breakdown of the concept and why it matters to everybody involved in clinical research.
By definition, a PD is anything that causes one or more subjects to deviate from the strictly defined procedures and events laid out in the protocol. You might imagine then that it wouldn’t be difficult for this to happen – for example, if a subject gets sick and cannot attend a study visit when they’re supposed to, that would be a PD. That wouldn’t be anybody’s fault, it’s simply something that couldn’t be avoided, but it is still a PD. More seriously if a pharmacy fridge fails without anyone noticing, and a subject is given a medication that might be ineffective, that would also be a PD.
There used to be a term of Protocol Violations (which were deemed more serious) and PDs, but that guidance has since been clarified/rescinded and now all should simply be reported as PDs, and further categorized into Important or Not Important. Important PDs are those that would impact the rights, welfare, or safety of subjects, or would potentially negatively impact the integrity of the data. Non-Important PDs are divergences from the protocol that do not significantly impact subject safety or data integrity. In part, I think this was to reduce the perception that PDs were a punitive act against the sites and Investigators. Investigators often feel that they are being blamed for events that are outside of their control (for example, sick subjects not showing up), or equipment that doesn’t work. There is a fear, which is in part founded on the reality that they are wholly responsible for the research conducted, that too many PDs will lead to their ability and integrity being called into question. It is true that in the very worst cases an IRB can revoke an Investigator’s ability to conduct scientific research, but in more than 99.99% of instances I would say that the PDs are meant as an administrative and a statistical tool, and certainly are never intended as punitive.
The true purposes of detecting PDs fall into two broad categories – regulatory, and operational. From a regulatory perspective, it is absolutely crucial to detect and identify a “per protocol population” – the group of subjects who, as best as reasonably possible, followed the protocol as agreed to by the regulatory body (e.g. the FDA in the USA). Without this, the sponsor for the study cannot possibly go back to the FDA and say “Look, we proved our drug is safe and effective – please approve it for us!”. If too few subjects followed the protocol, as agreed, then the FDA will simply refuse and tell the sponsor to go back and get more subjects. This is why it is so crucial that Investigators do not willingly deviate from the protocol, even if (and I cannot stress this enough) they would do something different under the normal standards of medical care. Losing one subject here and there is not too great a problem, but losing hundreds (or even thousands) of subjects due to PDs can be devastating to a clinical trial. For this reason some studies retain the “violation” distinction for the most serious PDs that would drop a subject from the per-protocol population, whereas others might opt for a designation of Major or Minor PDs. The distinctions are crucial, and must be clearly defined by the entire project team, including the Clinical Operations, Medical Monitoring, Data Management and Statistical team members. Many of the PDs will be detected by Clin Ops during their site visits or through remote data monitoring; a large chunk are detected during Medical data review (for example the use of prohibited medications, or potential exclusion criteria in medical history); and without the input of a statistician and data manager it isn’t possible to properly assess the impact of these PDs on the final analysis of the clinical trial. In some cases, sites may be asked to track additional information, or the data management team may have to code custom programming to identify and track certain PDs. In one study I was on, the out-of-window visits were subdivided into Major or not depending on how far out of window they were, and only for certain key study endpoints. This is the kind of nuance that can’t be simply tracked as an “out of window” visit – it needs to be “out of window for Visit X by Y days”, and would absolutely need custom programming (and very clearly written protocol deviation guidance) to detect, if the sponsor wanted to go down that route.
I was involved in a company-wide initiative to update and improve our Protocol Deviation process, to optimize the process and understanding of each team member on their role. Medical Monitors in particular have to weigh in on Important PDs, which are defined as any that might impact subject safety or data integrity – ultimately we have to decide if that subject should be dropped from the study or if they may continue. Sponsors often don’t appreciate the distinctions between the different levels of PD, and the work they entail, so it’s important to communicate that clearly during study start-up. PDs are also very much study-specific – for example an “expedited PD” may require the Medical Monitor to contact the site and intervene on an urgent basis, but it makes no sense to mark certain PDs as expedited in a single-dose study (such as a vaccine study) when the PD would be detected long after the subject was dosed. It also makes no sense to mark PDs that would be detected by the Medical Monitor as “expedited”, because they already know about them! If a missed study visit occurs then it’s reasonable to track that as a single PD, and not necessary to track separate PDs for every missing procedure during that visit (yes, I’ve seen this done inadvertently!) The goal of this process improvement was to streamline and align the PD process between all the relevant team members, and ultimate save time and money throughout the entire study timeline.
The second reason for detecting PDs is operationally – the Clin Ops team monitors and tracks PDs, and especially important is the categorizing of PDs. For example, if they find that there are many PDs for inclusion/exclusion criteria, it might be that the protocol is unclear and needs revision. If they find that one site has many PDs compared to their peers it might signal an issue that requires site staff retraining – and the flip side of course is that if a site has very few or no PDs that they aren’t being truthful in their data reporting… Ideally these are reporting back to the Sponsors regularly throughout the study, although I have come across some smaller biotech companies who have asked merely for updates perhaps one time during the study, and once at the end. In my opinion this is a recipe for disaster – it means that the operational benefits of the PDs are diluted, if not lost, and it also means that potential revisions to the protocol that could improve the quality of the data (or subject safety) are not made. The very best companies use PDs as “constructive criticism” to optimize their study sites and protocol. PDs can also be an absolute bear to properly collect and categorize, and the worst thing that could happen to a study team is to discover right at the very end of a study that there are hundreds (or thousands) of PDs to address when there are looming deadlines of database locks.
There are two further things I want to highlight about PDs. There is a hierarchy that actually stretches very high up – PDs can be at the study level, the country level, the site level, or the subject level. Study and country-level PDs are extremely rare. Site level PDs do occur, but they are often misidentified, and that can cause a lot of work. By definition, a site-level PD affects all subjects at that site. This is a statistical definition, not a common-sense definition. For example, a broken pharmacy fridge might be incorrectly identified and recorded as a single site level PD (failure to adequately maintain and monitor study equipment) – but the problem then arises in the final analysis, where EVERY subject from that site would be tagged with that PD! In truth, the clinical monitor who visits the site has to correctly identify the subject(s) impacted by the event, which usually means tracking specific dates, subject timelines, and drug deliveries to figure it all out. They would have to identify and report PDs on the affected subjects, and ONLY the affected subjects. This might mean reporting 23 separate PDs (one for each of 23 affected subjects) instead of one site level PD, unless the site has only enrolled 23 subjects! But trust me I say this is the correct way to do it – this is exactly how the FDA will ask the events to be captured if they were to visit the site for an audit. I perhaps misspoke above when I said that the worst thing that can happen is for a last minute deluge of PDs just prior to database lock – imagine a deluge of PDs after database lock because of an FDA audit findings…
And finally, the reason for the meme I made above (which I have actually presented in Investigator training slides…). Sites often ask for “exemptions” or “permission” for a PD ahead of time, for example if they know that a particular subject is going to be out of town and miss a study visit, or if a subject has a prohibited medical condition but would otherwise qualify for inclusion in the study. The thought is, if they ask ahead of time they won’t be “dinged” with a PD.
It is a very, very, very bad idea to grant exemptions to PDs. As I said above, PDs are there to ensure data integrity and that the per-protocol population is sufficient to be submitted for regulatory approval. If a significant PD is granted ahead of time, the entire clinical trial is put at risk. I was trained to never, ever, grant a PD exemption. We can acknowledge that a deviation has (or will) occur, but it will be reported, and it will be categorized, and if need be the local IRB will also have to hear about it. Now, there are some sponsors that will grant PD exemptions on a case-by-case basis but that is their risk to bear. Not every event reported as a PD is actually a deviation when fully reviewed, and it isn’t unreasonable to void a PD that shouldn’t be there, but they would have to defend that decision should a regulatory authority question it, and if you don’t think that a regulatory authority will detect discrepancies in individual protocol deviations and subject data, then you haven’t witnessed a regulatory audit… What the site/Investigator really needs to ask is “Can this subject continue in the study, should this PD occur?” That’s an entirely different question, and is probably what the site is really wanting to know, but even if the answer is “yes” then every effort needs to be made to follow the protocol – the Investigator literally signed a legal document saying they would do this (I talked about Investigator responsibilities last week…)
To summarize – PDs are inevitable, even if they should be avoided as much as possible, and they are very important tools used during the conduct and in the final analysis of a clinical trial. Clear PD guidance should be established very early on in the study start-up to identify areas of risk and mitigation steps, and PDs should be routinely reviewed with the sponsor so that course corrections or staff retraining can be done as needed. Proper categorizing and coding of PDs (Important, Non-Important, Major, Minor, Expedited…) will dramatically improve the quality of the data and project workflow for everybody involved. Sites should not fear PDs, and they absolutely should not attempt to cover them up, but please don’t ask for exemptions.
Drop me a line, or follow this blog, if you want to learn more about PDs and how best to avoid or manage them.
I chose this rather banal title firstly because it is descriptive, but secondly it draws attention to the seriousness of what it means to be an Investigator on a clinical trial. Following up from my first post on this topic, here I’m going to go into more detail on the role and responsibilities.
21 CFR 312.60 – An investigator is responsible for ensuring that an investigation is conducted according to the signed investigator statement, the investigational plan, and applicable regulations; for protecting the rights, safety, and welfare of subjects under the investigator’s care; and for the control of drugs under investigation. An investigator shall obtain the informed consent of each human subject to whom the drug is administered, in accordance with part 50 of this chapter. Additional specific responsibilities of clinical investigators are set forth in this part and in parts 50 and 56 of this chapter.
My first experiences as an Investigator actually stretch back to my earliest days in clinical research in 2004. I was in a kind of twilight zone for a little while, technically hired on as a study coordinator but, with my medical and PhD degrees, I was actually named and delegated responsibilities as a Sub-Investigator on several clinical trials. The training that we all have to do to undertake human subject research makes it very clear how serious and important the role of the Principal Investigator is. The preamble statement from the USA Federal law must be fully comprehended. “An Investigator is responsible for…” Do you really know what that means? If a study coordinator accesses medical records improperly for subject screening, the Investigator is responsible. If a nurse draws the wrong number of blood tests for a specific study visit, the Investigator is responsible. If a pharmacist dispenses the wrong dose of study drug for a subject, the Investigator is responsible. Investigators can (in fact, they must) delegate tasks to study site personnel who are properly trained and qualified to perform those tasks, but delegation does not absolve them of responsibility. This is a significant increase even from the supervisory role that many physicians are in, whether it’s teaching residents or fellows, or supervising Nurse Practitioners or Physician Assistants. As a Principal Investigator the Physician is held responsible even for tasks that they themselves might be incapable of doing (for example, study drug dispensing, or certain types of clinical testing).
This requires a seriousness of mind when a physician decides to undertake clinical research, and in addition it requires considerable support. Whenever I am asked about whether a physician should become an Investigator, my very first thought is “do they have enough support staff?” Having been a study coordinator, and having worked with study coordinators of my own, I have to say that regardless of how good a researcher might think they are, they will absolutely fail in running a clinical trial unless they have a good (if not great) study team. The administrative tasks associated with study start-up alone are Herculean – reviewing the Clinical Trial Agreement, Protocol, and Investigator’s Brochure, adapting the informed consent form (and in some cases, the protocol itself!) to local standards for IRB submission, completing the IRB submission (and any other review boards required), negotiating a budget, organizing sub-Investigators and collaborators, and ensuring adequate space and equipment exists to see subjects, perform procedures, and collect all the required specimens. All of that is before you even see a single subject. If you are able to get all that done, then a representative or two from the sponsor or contract research organization will visit to activate the site. A site initiation visit (SIV) is generally several hours of time for training, inspections, and administrative paperwork such as the delegation log, training logs, and FDA1572 “Statement of Investigator” form. Most physician Investigators are hard-pressed to even make it to an hour of the SIV – never mind attend the entire visit. I was fortunate to have excellent study staff to work with, and in fact a dedicated Clinical Trials Unit (with their own clinic space and lab) existed to help Investigators throughout the institution. My coordinators included a nurse, and I had a lab tech and study pharmacist team to use too. I was very well supported!
Aside from needing the appropriate mindset to conduct research seriously, and a solid team, there are several areas where Investigators can let their site down, even with the best intentions to heart. Perhaps the most frequent way in which Investigators can get into trouble is agreeing to perform a study that they cannot properly execute. When an investigator is initially approached for a study, they should perform a genuine, reality-based assessment of the feasibility of the protocol. If the blood tests require a -80C freezer, and they don’t have a -80C freezer, then they can’t agree to do the study until they buy one. If the study requires that subjects stay for 8 hours getting pharmacokinetic blood tests done, but their clinical trial unit closes at 4pm, then they can’t agree to do the study. If they only see 1 patient with that specific diagnosis every few months, then they shouldn’t commit to enroll 10 patients in a year. That last issue occurs again and again…I think in a (very) misguided approach to convince the sponsor to allow them to sign-up because they’ll be a “good site”. In truth this is a bad idea, for several reasons. Firstly, site budgets are often written based on the expectation that a certain number of subjects will enroll, and some overhead costs are averaged out over the entire patient mix. Obviously the specifics vary by institution and study budget, but I have certainly heard of sites getting into financial trouble because the investigators would consistently over-promise and under-deliver. Secondly, it makes the investigator look bad – because as much as they can promise the moon, when reality hits they can’t hide it. The CRO and Clin Ops teams will be pushing hard for enrollment, because they in turn are getting pushed by the sponsor for enrollment, and you can bet your bottom dollar that the sponsor is pushing because their Board of Directors and shareholders are pushing for enrollment! Do. Not. Over-promise. Thirdly, and this is a fun little factoid – but the average and typical enrollment data is publicly available. We can tell if a site looks like they’re over-promising, because their enrollment projections will be vastly different from those seen elsewhere in similar studies. I have absolutely seen research sites and Investigators removed from potential study site lists because they were not thought to be realistic.
Investigators can also negatively impact a study by managing their subjects too much like a treating physician. I have heard over and over again something like “Oh, yeah we identified 3 eligible subjects, but they’re not due back in clinic for 3 months.” What? No! So in 3 months you might talk to them about the study, you might give them the consent to review, and maybe they’ll bring it back and sign it in another 3 months? Talk to them over the phone, now, tell them there is a study they might be eligible for – give them any websites or other information (IRB-approved, of course), and you can even email them the consent to read over ahead of time. Bring them in EARLY for a screening visit, separate from their next official medical appointment, go over the consent in person and answer any questions, and if you’re lucky they’ll sign up next week! There is a sense of urgency in clinical trials that simply doesn’t exist in routine medical care. Do not wait to discuss research with your potentially eligible patients and families.
After enrollment, do not manage clinical trial visits and procedures as you would medical care – blood tests might be timed down to the nearest minute, study visits often have allowable windows of only a few days early or late (big tip to schedule study visits early in the window, in case anything happens and you have to delay). You have to be very well organized, and again this goes back to a diligent study staff team. For one clinical trial I was a coordinator on, I created a spreadsheet for all 191 subjects with built-in math to figure out all the required telephone calls and visits that had to be scheduled. A lot of studies these days have similar tools built into the electronic data capture systems to assist site staff with this, but I started back in the day of paper records for clinical trials… In any case, find a system that works and is reliable, and use it! The risks of a lack of diligence and organization are, at the least, protocol deviations and poor data. At the worst, the site can be shut down and the Investigator may be prohibited from conducting research. I have personally seen sites that were put on hold due to serious breaches in Good Clinical Practice (GCP – the rules regarding subject safety and clinical trial execution) that placed subjects at potential risk of harm, all due to a lack of diligence from the Investigator (remember “Clinical” in this context refers to medical research and clinical trials, not standard medical care).
Every Investigator should have undertaken training in the principles of GCP, in fact it is one thing that is repeated for every clinical trial training regardless of whether or not an Investigator has done it before! This training is not entertaining – it is snooze-worthy – but it is very important. The physicians who don’t pay attention to it are the very same ones who are immediately asking for permission for protocol deviations or to skip certain study procedures or visits “because they’re not needed”. If it’s in the protocol, it’s needed. I absolutely urge Investigators, whether would-be, newbie, or seasoned veterans, to pay attention when it is being done. Clinical research certainly isn’t something that should be done in a haphazard or half-hearted way. There is also no room for ego – Investigators and other study staff will make mistakes, Protocol Deviations will occur, misunderstandings will happen. The extremely high standards and rigorous oversight that are required for clinical trials is something that most physicians aren’t used to in their day-to-day practice of medicine, and it can often be misinterpreted as a personal attack or insult to their intelligence. The fact is, we’re really all on the same page, trying to get the best possible data, and keep the subjects as safe as possible.
On that note, the Investigators are responsible for the safety of their subjects. In that regard the opinions and actions of the Investigator matter a great deal. If an Investigator deems that a subject should be withdrawn from a study, they can do that. If an Investigator grades a particular adverse event as mild, moderate, or severe, then we generally rely on their assessment as the clinician who saw the subject (there are exceptions for specific laboratory results or protocol-defined criteria). Investigators assess whether an adverse event is related to the study drug or not. While the Medical Monitor and sponsor can (and often do) request clarification or confirmation of a specific finding, and sometimes even disagree with the Investigator, the Investigator’s assessments are still reported and are incredibly important. Some types of adverse event require very rapid (7 day) reporting to regulatory agencies, and that all hinges on the Investigator’s assessments. It is not unusual for Investigators to reach out to Medical Monitors for clarification or advice, but the Medical Monitors cannot provide patient care and cannot really direct an Investigator to do one thing or another. We can provide information and clarity on the protocol, insight into what the sponsor might think on a particular decision, and discuss any potential protocol deviations that might occur, but ultimately it is the Investigator that makes the final call. I have completed many telephone conversations with the line “I support your decision”.
In that regard I will discuss one final thing that Investigators do that causes issues, albeit rarely – subject unblinding. In randomized clinical trials, the subjects and often Investigators (even the Clin Ops teams and Medical Monitors) are all blinded and unaware of treatment assignment. This is so that no-one contaminates or biases the data from assumptions made of the treatment being given. However, it also happens that subjects occasionally get adverse events that may or may not be study-drug related. There is generally a clause in the protocol that allows for emergency unblinding under certain specific circumstances. That last bit is crucial – because unless it is genuinely thought that (a) the event is linked to the study drug and (b) knowing the treatment assignment will affect the medical management of the subject’s adverse event, there is no reason to unblind the subject! If on month 4 of a vaccine study the subject has a severe stroke, what would you possibly do differently with them, knowing what vaccine they got 4 months prior? Would you use a different brand of tPA? Would you shorten their rehab knowing that they “only” got placebo? No, it wouldn’t matter one iota. Trust me – the subject will be unblinded as part of the final analysis – and often studies have unblinded safety monitoring teams who will look at these type of events separately from everybody else on the study (I have sat on both blinded and unblinded safety monitoring committees for various clinical trials). There is very rarely any rush to unblind as an emergency, and if that is done it actually risks contaminating the data and losing that subject from the final analysis. By all means use emergency unblinding when necessary, but think clearly on whether or not it would actually change the management of the subject or whether it would “just be nice to know”. Do not risk the entire drug approval process just to appease your personal curiosity. It is perfectly reasonable to have a discussion with the Medical Monitor and the sponsor as to whether or not an unblinding should occur, and that can wait until the dust has settled and more information is at hand. Remember, an Investigator can withdraw a subject from a study at any time, and there are allowable reasons to stop study drug while still continuing in the study for safety follow-up. Neither of those options requires unblinding.
Those are highlights of the much broader and more nuanced role of a clinical trial Investigator than I can cover in a single blog post. What I hope I have imparted though, is a sense of how seriously the role should be taken. Investigators are literally the beating heart of clinical research, hugely important, with a great deal of trust given to them, and I found the role to be an incredibly rewarding aspect of medicine, both personally and professionally. I’ll cover how you actually become an Investigator in another post.
It is a common misconception among physicians that engaging in medical research (or clinical trials) is not much different from practicing medicine – I’ve seen the question may times along the lines of:
“I’ve been asked to be an investigator for a clinical trial. How much work is it beyond finding patients, and how much will I get paid?”
There are so many aspects to this area that I’m actually going to devote several separate posts to this. I’ve thought for a long time that it would be a great idea to draft some educational material to help sites, subjects, and study staff to navigate the complexities that are clinical trials, and here we are.
I have been involved in clinical research for about 20 years now – covering everything from being a study coordinator recruiting subjects, collecting blood specimens, and completing case report forms, all the way through to being a medical monitor responsible for the safety of literally thousands of subjects, and ensuring that the data collected is as good as we can get. I have seen drugs fail, companies fall, and I’ve also seen new approvals get to market. It’s an incredibly rewarding career.
The art of medicine though requires a high level of insight and a degree of imagination – I have used a phrase along the lines of “Rules are for the protection of the weak and the guidance of the wise.” – usually right before I break a rule of some kind 😁. Physicians are in fact expected to think outside of the box and imagine what might be the diagnosis, and they have access to an ever-expanding arsenal of medical treatments to choose from for their patients (thanks to clinical trials – hint hint). Documentation is proscribed and expected, but the specific language used has considerable leeway. As strict as the framework of practicing medicine is, it’s still not that bad when you think about it.
Clinical Trials are a whole other beast. When an investigator agrees to oversee a clinical trial, they actually have to sign a legal document agreeing to follow a specific protocol for that study. This protocol isn’t just a plan to conduct the research – it is a highly detailed and specific document, with many ancillary documents, detailing every step of the subject’s journey from screening until closeout, and what might happen along the way. It is a document vetted by statisticians, clinical operations (people who work with the sites to execute the protocol), data managers, regulatory and legal experts, and independent physicians (protocol review is a routine part of a medical monitor’s job). The protocol has to be signed off by the FDA or other regulatory body at the country-level, so they agree that it doesn’t put subjects at undue risk and has all the required steps to meet the study objectives. As a simple example, enrolling too many subjects might put people at unnecessary risk, whereas enrolling too few subjects might make it statistically impossible to show that the clinical trial has succeeded. At the local level, every site has a Institutional Review Board (and sometimes a Scientific Review Board as well), and they also have to review and sign-off on the research as being appropriate. Everything that a subject might potentially see has to be vetted to ensure it is easy to understand, fully explains the risks and benefits of consenting to the research, and isn’t coercive. Every member of the study team has to have evidence of the proper training and qualifications to conduct not just research, but this protocol specifically.
Clinical research is so tightly regulated that an entire section of international (International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) Guideline for Good Clinical Practice (GCP) ) and United States law (various parts of 21 CFR) is devoted to its conduct. The point being, that when an investigator agrees to conduct the study according to the approved protocol they cannot change it. They don’t get to chose when, or if, a subject shows up for a visit, they don’t get to chose the treatment (unless that is defined in the protocol), they don’t get to decide which tests are or are not performed – not unless there are very clear reasons and exceptions laid out. One obvious reason is for immediate subject safety needs, but that is exceedingly rare. I’ll talk more about Protocol Deviations and what they mean in a later post…
From the subject’s point of view though, I think it is crucial to appreciate that clinical research is by its very nature, and due to the scientific and and legal constraints placed upon it, incredibly strict and well thought-out. Clinical research is not a case of “let’s try this and see if it works”. I do think that subjects are aware of the second point about clinical trials – that they often provide access to new and as-yet unavailable treatment options. I know that the investigators are very mindful of this fact, and in truth one key motivator for being an investigator is in making these treatments available to their patients right away, and in contributing to the greater good by hopefully bringing a new treatment to market to make it available to all.
From the Investigator’s point of view, they should not undertake clinical research unless they are prepared to be held to an incredibly high standard – far higher than they are used to in the day-to-day practice of medicine. That is the price to pay for getting access to brand new and cutting-edge treatments. We’ll go over the specifics of the investigator’s role and responsibilities in a later post, but suffice to say – don’t do it for the money 😉.
MRSA, affectionately pronounced “mur-sah”, and the abbreviation for “methicillin resistant staphylococcus aureus”, has become the epidemic of our time.
Everyone thinks they know what it is. Few actually have a good handle on what it really means, especially with kids.
MRSA was first described back in good old Blighty in the 1960’s, not long after the drug methicillin was released in an attempt to combat the rise in penicillin-resistant staphylococcus aureus. In the modern era methicillin is no longer available, due to kidney toxicities that are much less in the current selection of anti-staph penicillins (nafcillin and oxacillin), but the MRSA tag remains in use.
In practical, and literal terms, it simply means that the organism in question is resistant to that particular antibiotic. Well, whoopdedoo. Lets just pick another. Except you can’t. The way in which staph becomes resistant to methicillin is through the production of an altered protein that renders the bug resistant to EVERY antibiotic in that entire FAMILY of antibiotics. Penicillin? Gone. Cephalosporins? Gone. Beta-lactamase inhibitors? Useless. Carbapenems? Fat chance.
So you go to another class – quinolones, aminoglycosides, tetracyclines, sulfonamides – but none of them are especially active against staph and…wait for it….MRSA is often resistant to these drugs too.
The first place in which MRSA was discovered was in healthcare settings – long-term care facilities and hospitals. The overuse and abuse of antibiotics selected for strains of bacteria that had acquired all sorts of resistance genes. In fact, the gene for hospital-acquired MRSA is a multi-segment behemoth that carries with it all sorts of additional genes, so the whole lot are inherited together. MRSA infections were associated with severe, invasive disease and death, usually in adults already weakened by other diseases. Due to delays in starting the right treatment, and being forced to use second-line, less effective drugs like vancomycin, MRSA infections add to hospital stays and healthcare costs. Like to the tune of $60,000 apiece.
Just as the world was getting used to dealing with MRSA in hospitals, we started hearing about it in the community. People were showing up with skin abscesses, boils and other infections that were, in about half of cases, growing out MRSA. Worse, they didn’t seem to have any link to the typical risk factors of diabetes, renal failure, cancer, prolonged hospital stay etc. And even more scarily, this was being seen in kids.
But they’re different from the old hospital-acquired MRSA cases. The community MRSA gene cassette is far smaller, lacking the resistance genes of the hospital MRSA. We have a small, but reliable list of antibiotics to use to treat it. Invasive disease is unusual, skin infections are the norm. I have not, yet, seen a real hospital-acquired strain of MRSA in a child. I have seen a few kids pick up MRSA while in the hospital, but it’s always been the “community” strain brought in by visitors, family or other patients.
Diagram of MRSA gene cassettes – hospital (top, types I thru III) versus community (bottom, types IV thru VI)
Right now, I see a steady stream of kids with MRSA in my clinic and in the hospital. By far the vast majority are recurrent skin infections, often bouncing around various family members. Parents, reading up on MRSA online are understandably freaked out. Friends and relatives shun their kids, for fear of picking it up. Furnishings and furniture are steam-cleaned and thrown out, course after course of an antibiotic is given to treat each infection, but they never seem to go away. Even pets end up getting “swabbed” and tested in the lab, and yes, some are sent on their way as the presumed culprit.
None of this matters.
The truth of the matter is, while MRSA does indeed cause a good chunk of these kind of infections, it’s not got the hold on it. Just as many regular, sensitive staph (MSSA) cause these things. Fully one third of the population carries staph aureus on them – and clearly one third of the population is not suffering from recurrent skin infections. Carrying staph doesn’t mean you’ll get infections. And, annoyingly, you can test negative for staph from a swab (typically done from the nose) and still have infections elsewhere, such as the armpit, legs, or buttocks. We’re exposed to staph everywhere, all the time – and we mostly don’t even know it. That’s if we don’t have it already.
The reason why the skin infections keep happening is due to an entirely separate set of genes, related to immune evasion and skin invasion, which although more common in MRSA are also in some MSSA. (They are, interestingly, mostly absent in the hospital MRSA strains.) The way to get rid of it, if the levels are high enough for these infections to keep happening, is simply to decolonize the skin. That can be done with chlorhexidine washes and bactroban nasal ointment (a two week protocol), but you also have to prevent re-colonization, a more difficult proposition. Bathroom surfaces need to be bleached, towels washed daily (paper towels for hand washing) and EVERYONE in the household needs to have this done. There’s no point focusing on little Johnny with his butt abscesses if mommy and daddy, who are carriers, give him a hug and spread it back.
I never promise that with this approach staph will go away entirely. What we do know is that, if everything is done at once, you CAN eradicate staph at least temporarily from the skin. What we also know is that a third of the population carries staph….so wait long enough and you’ll get it again. I hope to merely reduce the frequency of outbreaks.
In my experience…this seems to work. Except in situations where kids have severe eczema or other skin issues, or where they’re not following EVERY step of the plan, I generally don’t see these kids back again.
So that’s prevention – what about cure? How should we treat these kinds of infections when they do show up? One drug that has seen a resurgence of late is bactrim – trimethoprim-sulfamethoxazole. A combination drug that is designed to inhibit the bacteria’s use of a chemical called folate which is a key component of DNA creation. It sounds good on paper, stop the bacteria from growing and it’ll die. In the lab, staph is often 99% sensitive or more (good odds when your risk of resistance to other staph drugs is around 50%!). The trouble is, in an abscess there is pus. And pus is basically dead and dying cells and bacteria. That’s a lot of DNA hanging around. Using bactrim in that setting is a lot like telling a farmer he can’t grow any more food, but putting him in a grocery store. He ain’t gonna starve any time soon. Bactrim also ignores the risk of strep, which are the other cause of skin infections and which are inherently resistant to bactrim. As such, deliberately targeting MRSA with this kind of approach actually results in MORE treatment failures than using a simple staph drug like cephalexin, even though that shouldn’t work with MRSA! You WILL get treatment failures with cephalexin too of course, and some with the other drugs like clindamycin, doxycycline etc. But it’s as if one should ignore the MRSA when planning your treatment. Drain abscesses (you usually don’t even need antibiotics if you do that) and then use a regular “skin infection” drug to minimize side effects and maximize your chances of success. These days we have NO ideal drug for empiric therapy of skin infections – but we certainly do worse if we panic about MRSA and try to tackle that first. Weird.
Of course sick patients are a different matter – even though the risk of severe invasive disease is low, the consequences are dire. You should ALWAYS cover a very sick patient with vancomycin or other MRSA drug until you know what you’re dealing with.
So I don’t panic about MRSA. I see it all the time. It’s annoying. It’s rarely dangerous. I know that if you focus on it to the detriment of the regular staph and strep you do worse. If someone is a carrier or has an active infection, good hand washing and covering any draining sites is enough to keep it at bay. No need to decontaminate entire schools just because a kid has been found to have MRSA. No need to put everyone on vancomycin if they’re not sick. And if they ARE sick, please don’t use vancomycin by itself, cos its a crappy drug and we only use it because we have to. Don’t bother swabbing just to check for carriage – positive results aren’t worth acting on unless the patient is sick (or, perhaps, due for surgery soon…that’s a whole other issue), and negative results are useless if the patient is actively infected. Deal with the infections, attempt decolonization, move on. Repeat if necessary.
MRSA – it’s a pain in the butt. And not just for the patients.
For those who haven’t been under a rock recently, several parts of the US have seen a surge in pertussis cases. Much of this has been (fairly) blamed on anti-vaccination efforts to reduce herd immunity and the cocooning of vulnerable infants. But that’s not the whole story.
Interestingly enough, it’s now clear that the DTaP vaccine (diphtheria, tetanus, acellular pertussis) doesn’t provide long-lasting immunity. We had some clues with this as an awareness grew of pertussis in older teens and adults, fueled in part by vastly improved testing for pertussis (PCR versus ‘cough plates’ for culture) and a recognition that pertussis in older kids and adults didn’t look like the classic ‘whopping cough’ that youngsters got.
A booster dose of pertussis vaccine was recommended, included as part of the tetanus booster (the new Tdap vaccines). Recent outbreaks seemed to focus on the group of kids aged 10-11 years of age – when vaccine immunity was waning, but just before their Tdap booster – but the recent outbreak in Washington State has involved even 13-14 year olds, who did get their booster!
The question then should be – why does the NEW vaccine work LESS well? The answer is because it is SAFER.
The old DTP vaccine began to get a bad reputation for neurologic disease – in fact a contraindication still exists to withhold pertussis-containing vaccines in kids who develop neurologic issues after pertussis vaccination, even though the vaccine is different. The old DTP contain literally thousands of antigens, based as it was on a relatively impure cocktail of cell culture fragments that contained the pertussis bacteria. It caused a fair amount of immune reaction, and clearly was linked to febrile seizures.
Several high-profile cases of apparently neurologically damaged children (leading to the formation of some of the early modern anti-vaccine movement) pushed the vaccine manufacturers to create a cleaner vaccine, an ‘acellular’ pertussis vaccine, which is why we have DTP and DTaP. DTaP doesn’t have the same link of febrile seizures and no link to any neurologic issues (interestingly, as detailed in Paul Offit’s book on the history of antivaccine junk science, neither do any of the original DTP kids…it was all a big screwup). Tdap is even less immunogenic as it has slower concentration of antigens – you can tell this because it has a small “p” instead of a big “P”. True story.
The trouble of course is that by having a less inflammatory response, with far fewer antigens, the protection is less. The original DTP vaccine contained more antigens than the ENTIRE modern vaccine schedule does, several times over. Any statement about ‘too many too soon’ is pure bunk – our kids are exposed to fewer vaccine antigens in their entire schedule that we were in one vaccine.
This story highlights several points – firstly, contrary to antivax propaganda, not only are there mechanisms in place to detect and respond to potential vaccine side effects but there are CHANGES made to the vaccines in an attempt to keep people safe. (Probably the only positive thing to come out of the antivax movement is the establishment of the Vaccine Adverse Event Reporting System, VAERS). Secondly, there are compromises to be made – more effective sometimes also means more side effects, so if you want to lower one you may end up lowering the other.
There is also data from Europe that as the vaccine strains of pertussis wane, there is strain replacement with potentially more virulent strains. So although we are seeing fewer cases, those cases we do see may be more serious (this finding hasn’t yet held true for the US…as far as I know).
Sadly, those who believe antivax propaganda are not usually stupid – if anything they tend to be more educated than average, and well read. They just read the wrong things. Not everyone can go to medical school after all.
Then again, even that isn’t foolproof. One of the original antivax “Expert” witnesses from the UK trials that showed the DTP link with neurologic illness to be wrong went on to further his infamy with AIDS denialism.
Much of the details on the stories of the DTP and DTaP history are in Paul Offit’s book – Deadly Choices, which I highly recommend. In it he not only details how antivax proponents twist science and the facts to suit their case, but also how they nearly brought down the entire US vaccine industry through irresponsible and indefensible litigation. The vaccine WORKS to reduce serious illness from pertussis and undoubtedly saves lives. It’s not perfect, no one has ever said a vaccine was perfect – at least, not unless they were trying to make a point that it wasn’t…
When dealing with a newborn baby with a fever, those are words that strike fear into my heart.
Wait, what? You said no maternal history? Yep, that’s right.
Neonatal herpes simplex virus (HSV) is a topic that is full of counterintuitive statements, and far too much confusion. The wrong people get tested, the wrong people get treated, the wrong babies get worked up aggressively. When other docs diligently rattle off the “pertinent” aspects of the maternal history and clinical examination of the baby, in my mind I’m mostly saying “Don’t care, don’t care, don’t care….” before I interject and ask about test results that often haven’t been ordered.
Based purely on a numbers game, thanks to things like vaccination and Group B Strep prophylaxis, many early onset infections in newborns have been reduced. There is simply less infectious disease hanging around. But as a result, viral infections like neonatal herpes are proportionately becoming larger players – in some hospitals it is as common as bacterial meningitis. And neonatal HSV is a killer.
HSV comes in three distinct flavors – the least lethal is skin-eye-mucus membrane (SEM) disease. This is how many people expect to see herpes – a rash, typically vesicular (clear fluid-filled little blebs) and maybe some eye discharge or mouth sores. Most pediatricians, if they see something like this, appropriately freak out a little bit. SEM disease by itself isn’t too dangerous, and if treated properly is almost never fatal. Herpes is tricky though – in babies it can mimic other rashes, so you really do need a low threshold to consider it. ANY neonatal rash that doesn’t fit a normal neonatal rash (so know your neonatal rashes!) deserves a workup. There is nothing more sobering than to run a case of a neonatal rash by an ID doc and to have them tell you with complete sincerity that “You can save this baby’s life. Get them to an ER. Now.” Untreated SEM disease can progress to infection of the brain.
The most obvious presentation is disseminated disease – which weirdly enough can occur before SEM disease…first week of life or so. The kids are sick – really sick. They can be in shock, bleeding, in liver failure and struggling to breath as the virus overwhelms pretty much every organ system. The problem here is that even faced with this situation bacterial infection is considered immediately, and herpes can still be overlooked or thrown into the mix as an afterthought. Again, good neonatologists and pediatricians will be all over this from the start, having experienced their share of disasters in the past. Disseminated herpes is mostly fatal without treatment – and even with therapy about a third will still die, many of the survivors left with significant disabilities.
The last type of herpes infection is of the brain. Typically presenting later in the neonatal period (3-4 weeks of age, rarely later) herpes encephalitis of the newborn is devastating. Herpes causes a hemorrhagic encephalitis, meaning that it chews your neurons up into a bloody pulp. To a brain that has barely begun its developmental process, this is a disaster. Even if the baby survives they may be blind, deaf, paralyzed or have significant developmental delays.
From how I describe it above you might assume it would be easy to spot these kids. Well, it is – once it’s too late. The success of treating HSV depends to a large extent on how quickly you can start acyclovir – one of the few medicines we have that can treat viral infections (it’s pretty much only used for HSV). Acyclovir can shut down virus replication, but does nothing for those cells already infected. The difficulty with HSV lies in the nuances of the medical history.
Let’s try some armchair science for a bit. Would you, as a baby, rather get HSV from a mother who is having a recurrent outbreak of HSV, with low-levels of virus, and have her give you antibody protection through the placenta…or would you prefer to catch HSV from a mother who is having her FIRST outbreak (which may be without symptoms) with high-levels of virus and no antibody protection? Well, you may ask, how likely is that? The answer is Very. About 90% of all neonatal HSV cases come from mothers with no history of HSV. If your mom DOES have HSV and has a recurrent outbreak, the risk of transmission is about 5%. For a new case – its closer to 50%. Maternal history of HSV is relatively PROTECTIVE for the baby.
But the focus is on the mothers who test positive for HSV during pregnancy. They get put on valtrex (an oral version of acyclovir which is well absorbed), when it has not been shown to sufficiently reduce transmission. They may get a C-section, when that hasn’t been shown to help either (except maybe in the case of active lesions at the time of delivery…and even then it’s unreliable). The mothers who are HSV-negative are ignored, when they are those at highest risk of passing HSV to their babies. In an ideal world, their sexual partners should be tested and if THEY are positive THEY should be put on valtrex to reduce outbreaks and educated about the risks. But the fathers aren’t the patient….so nobody does that.
A big myth about HSV is that all babies with it look sick. Well, they do eventually – but to start with they look pretty normal. I have heard docs say that a baby looked “too good to tap” – meaning they didn’t perform a spinal tap to check for meningitis or HSV encephalitis. Or they don’t test sufficiently for HSV, or don’t start treatment with acyclovir while test results come back (these same babies are almost universally started on antibiotics for presumed bacterial infection). Published case series of proven HSV cases shown over and over again that babies with HSV present with relatively innocuous symptoms. “poor feeding” “fever” “sleepiness” before the more obvious symptoms of “shock” “seizure” or “respiratory distress”. Remember, by the time the baby is sick from HSV the damage has already been done, and you can only try to stop it from getting worse and hope the kid recovers. With bacterial infections we can kill them directly with antibiotics and the damage is usually secondary to the infection, and not because the bacteria are literally eating up your cells and blowing them apart as HSV does. Even with successful treatment, symptomatic HSV in babies has a slow recovery.
So how do you deal with this uncertainty? You can’t trust the mothers history, you can’t trust the baby’s physical examination or symptoms…what do you do?
My approach is to have a low threshold for suspecting HSV in neonates. ANY baby getting worked up for a possible bacterial infection needs to have a workup and empiric treatment for HSV as well. Babies with weird symptoms (especially rashes or neurologic symptoms) need to have HSV considered FIRST, before bacterial causes. HSV is not only potentially devastating – its treatable, and therefore the bad outcomes are preventable.
Fortunately the Committee of Infectious Diseases of the American Academy of Pediatrics has published recommendations – albeit in a rather inaccessible set of paragraphs. I can summarize them here though:
Spinal tap for HSV PCR of spinal fluid.
Liver enzyme testing for disseminated disease – chest x ray if respiratory symptoms.
Surface cultures from eye, mouth, rectum and any skin lesions.
Start acyclovir – do not stop until all tests are negative.
Do ALL of this this for EVERY BABY with suspected HSV.
Repeat spinal tap on kids with positive CSF to ensure clearance after 21 days – continue therapy if still positive.
A big mistake I see people making is in testing the spinal fluid to “rule out HSV” but do not doing the rest of the workup. Spinal fluid testing for HSV no more rules out SEM or disseminated disease than a urine culture can diagnose meningitis. I have seen cases missed (or nearly missed) because someone didn’t do the whole thing. You NEED the liver enzyme testing to rule out disseminated disease, and it matters. Treatment for simple SEM is 14 days – treatment for disseminated or CSF disease is 21 days. I have seen a handful of kids with positive CSF tests but with totally normal looking spinal fluid (eg no white cells, normal protein levels etc).
The trouble is HSV, as bad as it is, isn’t all that common among the hundreds of kids you will see with suspected neonatal infection. And many of THEM will be obviously HSV. So many kids get a semi-workup and we get away with it because “whoops, the CSF is positive!” and you treat for 21 days even though you didn’t check the liver enzymes.
But I’ve also seen the opposite – kids who were partially worked up and the diagnosis was missed, or delayed, or the severity was under-appreciated. All too often the “standard of care” let’s these kids slip through the cracks – which is inexcusable in my mind when there are experts who put it down in writing exactly how to work up these cases.
So let’s raise the standard.
Totally useless history:
Mom has no history of HSV
Mom got Valtrex
Mom got a C-section
Baby looks well
REAL risk factors for neonatal HSV:
Prolonged rupture of membranes
Active lesions at time of delivery
NO maternal history of HSV
Prematurity
Age less than 21 days
Unusual rash
Seizures or lethargy
“Sepsis” not responding to antibiotics (oops! too late! – better call your lawyer…)
Testing
CSF PCR
PCR/Culture of skin lesions, eyes, mouth, rectum
Liver enzyme testing
Chest X ray (if symptomatic)
Treatment
Acyclovir 20mg/kg/dose IV every 8 hours
Until all tests are negative (typically 2-3 days empirically)
14 days for proven SEM disease
21 days for disseminated or CNS disease
Nick Bennett MD 