The Phase I Clinical Testing Bottleneck

slow-it-downIn an earlier post, I suggested that an important step that could be taken to expedite herpes simplex virus 2 (HSV-2) Vaccine Development would be to “Streamline the Path to Phase I Human Clinical Testing of HSV-2 Vaccines.”

In today’s post, I wish to expand upon this point, and suggest that a “Compassionate Use Trial” of a HSV-2 vaccine might be one means to achieve a better balance between (1) the need to ensure the safety of all HSV-2 vaccine candidates tested in human clinical trials versus (2) the need for TIMELY TESTING of new HSV-2 vaccine candidates.

Over the past 25 years, a single HSV-2 vaccine approach (glycoprotein subunits) has advanced to human clinical testing, and has failed in 6 trials.  Recently, a new and completely different type of HSV-2 vaccine (Sanofi Pasteur’s ACAM-529 vaccine) was approved for Phase I Clinical Tests, which are to begin in late 2013 or early 2014.   At this rate of testing (i.e., 1 new HSV-2 vaccine strategy every 25 years), it could take us another 25 to 75 years to identify an effective HSV-2 vaccine if the ACAM-529 vaccine does not succeed.

In contrast, if we change the rules such that any and all reasonable HSV-2 vaccine approaches may be advanced to Phase I Human Clinical Trials as soon as they become available (i.e., as opposed to languishing on the sidelines for 10 years as ACAM-529 has), then it is likely that we could identify a safe and effective HSV-2 vaccine in a fraction of the time (i.e., 10 years or less).

This ridiculously long lag time between identification of a viable HSV-2 vaccine candidate and its advancement to a Phase I Human Clinical Trial is the key rate-limiting factor that explains why efforts to identify a clinically viable HSV-2 vaccine are proceeding at a snail’s pace.

Below, I offer one suggestion for what we might do differently in the future to streamline the path to Phase I Clinical Testing of all new HSV-2 vaccine candidates for which there is credible evidence that the approach is both safe and effective in animal models.

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CURRENT BOTTLENECK ON HUMAN TESTING OF HSV-2 VACCINES

When it comes to HSV-2 vaccines, I would suggest that the current FDA regulatory system lies somewhere between cumbersome and dysfunctional.  In particular, I refer to the process by which HSV-2 vaccine candidates progress from animal-based studies to human clinical trials in the United States.

At issue is the fact that by the time a scientist has worked out how to elicit robust vaccine-induced protection against HSV-2 in two species such as mice and guinea pigs, scientifically much of the “heavy lifting” is done, and it is simply time to “put up or shut up.”  Sure, some refinements will have to be made in terms of (1) cleaning up the HSV-2 vaccine formulation and removing impurities (i.e., producing a GMP, pharmaceutical-grade product) and (2) optimizing the vaccine dosage and route of delivery for humans.  At the end of the day, however, the primary thing that needs to happen is simply to immunize a small group of human subjects, and determine if a dose of the HSV-2 vaccine candidate in question (1) elicits a respectable immune response and (2) is well tolerated by human subjects.  This is effectively what a “Phase I Human Clinical Trial” of any HSV-2 vaccine would involve.

Such cursory tests do not address how effective a HSV-2 vaccine will be in the long term in a larger population of patients, but proceeding from Phase I Clinical Trials to test these larger questions in Phase 2 and 3 Clinical Trials has been less of a bottleneck in the past.

History informs us that in the United States, a single HSV-2 vaccine approach has made it to such Phase I Clinical Tests in the past 25 years.  Just like its close relative, varicella-zoster virus (VZV; which causes chickenpox and shingles), a live-attenuated HSV-2 vaccine would crush the genital herpes epidemic and bring this chapter of history to a close just as the live-attenuated VZV Oka vaccine has vastly reduced the burden of human disease caused by VZV.

Against this background (i.e., HSV-2 genital herpes should be vaccine-preventable), I find the current rate of HSV-2 vaccine development to be unacceptably slow.  I would vastly prefer the low and manageable risk of a well-designed, live-attenuated HSV-2 vaccine to the certainty that at least another 500 million people will contract new infections with wild-type HSV-2 and/or genital herpes if we continue our current pace of HSV-2 vaccine testing.

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WHAT DOES A PHASE I CLINICAL TRIAL ENTAIL?

There is no mystery, scientifically, regarding how to execute a Phase I Clinical Trial, and in principle such a trial could be planned and executed in less than 6 months, as they typically involve a small number of human subjects (i.e., 10 to 20).  In principle, a Phase I Clinical Trial is the equivalent of putting your toe in the water of a lake to figure out how cold it is before you jump in.  If something is really off with an Investigational New Drug, such as a new HSV-2 vaccine candidate, a Phase I Clinical Trial is your first look and opportunity to figure out if the drug is safe and/or well tolerated.  You may garner a little more information, but safety and tolerability are the primary focus of such trials.

Everyone can agree that it is imperative that a treating physician should disclose any and all potential risks of administering an investigational new drug to a human subject in a Phase I Clinical Trial.  Typically, this is done both verbally and via a 20- to 40-page disclosure form that (1) each patient signs to acknowledge the risks of being enrolled in a human clinical trial of an investigational new drug whose potential risks and complications are not fully vetted, and (2) this document spells out in no uncertain terms ALL of the potential adverse consequences that a patient might conceivably suffer as a result of being treated with an investigational new drug.  Moreover, each and every patient must be monitored closely after treatment to assure that adverse events do not occur, are recorded and documented if they do occur, and all of the resulting data is reported to a Data Safety Monitoring Board that oversees the Clinical Trial, and ensures that the trial is proceeding in a manner that is both safe and fully transparent.

I don’t think anyone questions the wisdom of all of these important safeguards in the structure of a Phase I Human Clinical Trial of a new drug or vaccine.

The problem lies in the many layers of bureaucracy that separate (1) a research team asking the FDA for permission to initiate a Phase I Human Clinical Trial and (2) the actual execution of the Phase I Clinical Trial.

I have spoken about this process with representatives of three major pharmaceutical companies (Merck, Sanofi Pasteur, and Crucell).  Each of them has offered a ballpark figure of 5 years and $20 million to satisfy the FDA evaluation requirements for a new HSV-2 vaccine, and each has questioned whether or not the FDA would ultimately be willing to allow a live-attenuated HSV-2 vaccine to advance to Phase I Human Clinical Trials.  Given these lingering doubts (“What if the FDA says no?”), none of these 3 companies expressed eagerness to shell out $20 million or walk uphill into machine gun fire as they sought to buck the prevailing wisdom that a live-attenuated HSV-2 vaccine would be “too dangerous,” and seek FDA approval for a Phase I Clinical Trial of this new vaccine approach.  Intriguingly, this reticence to pursue a live-attenuated HSV-2 vaccine as a pharmaceutical product is in spite of overwhelming scientific evidence that the approach I am proposing is (1) very safe in animal models, and is (2) 100 times more protective than the FDA-sanctioned HSV-2 subunit vaccines of the past 20 years.

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THE CURRENT CONUNDRUM

I don’t pretend to understand which specific facets of FDA rules, regulations, and procedures have every company with whom I have spoken unwilling to “go to bat” for a live-attenuated HSV-2 vaccine regardless of the proof that this HSV-2 vaccine would work 100 times better than what we have been doing.   However, common sense tells me that something is wrong when the prevailing belief system of FDA regulators trumps scientific observations and facts, to the point that 99% of scientists and companies are unwilling to act upon experimental evidence that, in no uncertain terms, indicates that a live-attenuated HSV-2 vaccine would serve as an effective genital herpes vaccine.

Regardless of the whys and wherefores, what is apparent is that the FDA has fostered a culture in which the pharmaceutical industry and business-minded scientists only consider “FDA friendly” HSV-2 vaccines that will get the green light to proceed to Phase I Human Clinical Trials.  This is why HSV-2 subunit vaccines are so prevalent today…..not because they work well, but because the FDA will approve their advancement to Phase I Human Clinical Trials.

The downside of allowing the FDA to effectively dictate HSV-2 vaccine development policy in the United States is simple; the FDA is not well versed in the rules of herpes immunology (which I have been studying for 20 years), which suggest that a live-attenuated HSV-2 vaccine may be the only approach that can yield a sustainable victory over HSV-2 genital herpes.  If this interpretation of the available evidence is correct (which I believe to be the case), then current FDA policies and procedures are effectively blocking human testing of the one class of HSV-2 vaccine that is actually capable of stopping the spread of HSV-2 genital herpes.

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THE NEED TO TEST ALL HSV-2 VACCINE OPTIONS IN PARALLEL

I expect and respect the fact that other scientists and regulators will not necessarily agree with the premise I propose above, that a live-attenuated HSV-2 vaccine is the only feasible approach to devise a clinically viable genital herpes vaccine.  Such discourse, disagreements, and debates are as fundamentally important to the advancement of science as good experiments.

Likewise, I would suggest that other scientists and regulators should respect the reciprocal possibility that a live-attenuated HSV-2 vaccine may indeed, as I propose, be the only approach that will work.

A good scientist knows that going into a problem from the front end, it is not possible to know what will happen.  Thus, good science boils down to (1) defining / considering all of the possibilities and then (2) figuring out which possibility is actually correct.

This has, and always will be, the landscape on which science is conducted.  We can pretend that HSV-2 vaccine research is different and that we “know” the next HSV-2 vaccine candidate will work.  However, I note that such claims date back to the 1980s, and yet we still lack an effective HSV-2 vaccine.

The simple reality is that, as in all other areas of scientific inquiry, we cannot know which HSV-2 vaccines will achieve a desirable balance between safety and effectiveness in preventing HSV-2 genital herpes in a clinical setting until we positively identify such an entity in a Human Clinical Trial…..period…..end of sentence.

For this reason, I would suggest that it is imperative that we devise a new paradigm that allows any and all HSV-2 vaccines that have proven, beyond a reasonable doubt, to be safe and effective in animal-based studies to advance in A TIMELY MANNER to Phase I Human Clinical Testing (i.e., in 10 – 20 human subjects).  There is no legitimate reason that the process of asking for permission to run such a small scale, Phase I Clinical Trial should require millions of dollars and 5 years of paperwork filings with the FDA.  Again, each year that we tarry and fill out FDA paperwork ensures that ANOTHER 20 MILLION PEOPLE WILL BE NEWLY INFECTED WITH HSV-2.   This is bad policy, plain and simple.  Stated another way, this is the scientific equivalent of sticking our heads in the sand and ignoring the available mountain of evidence that we are in the middle of a HSV-2 genital herpes epidemic.  The danger is not the HSV-2 vaccine candidates that have been proposed; the danger is our ongoing failure to develop a meaningful countermeasure to slow the spread of the HSV-2 epidemic.

It is time to change the system by which HSV-2 vaccines are allowed to advance to Phase I Clinical Trials so that we may, for the first time, honestly assess our available options for identifying a clinically viable HSV-2 vaccine today (i.e., not 50 years from today).

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COMPASSIONATE USE TRIALS OF NEW HSV-2 VACCINES?

I would suggest that people who live with frequent recurrences of HSV-2 genital herpes represent a group of patients who have not been adequately considered as a target population for Phase I Human Clinical Testing of new HSV-2 vaccine candidates.  First, I describe this patient population, and second I consider why this patient population should be granted immediate access to any HSV-2 vaccine that offers the hope of improving their condition.

Regarding the patient population in question, a significant fraction of patients infected with HSV-2 suffer from recurrent HSV-2 genital herpes disease that recurs so often that these patients essentially live with a CHRONIC VIRAL DISEASE.  Nearly all such patients are aware of the available antiviral drugs (e.g., acyclovir, famvir, valtrex), but these drugs are insufficient to control their chronic HSV-2 genital herpes symptoms.  Such patients may experience HSV-2 outbreaks that recur 10 to 20 times per year, and each outbreak may last for 7 – 14 days in duration.  Such patients describe only brief respites from active disease, and thus are best described as living with a chronic viral disease.  Aside from the visible symptoms of HSV-2 genital herpes, many of these patients also describe an episodic neuralgia (nerve pain) in the tailbone area, which is where HSV-2 permanently resides in the sensory ganglia that innervate the genital area.

One can imagine that such a chronic viral disease might take a tremendous toll on a patient’s psyche over a single year.  However, in some patients, this unaddressed condition of chronic HSV-2 genital herpes outbreaks lasts for periods of 5 years or more.

Some women report the onset of such symptoms associated with and on the heels of menopause.  For other patients, medical management of organ transplants or autoimmune diseases may require that a patient chronically take immunosuppressive drugs.  Chronic immunosuppression can compromise the body’s ability to keep the HSV-2 virus in check, and thus chronic outbreaks may become the norm.  In short, for a variety of reasons, some patients live with chronic HSV-2 genital herpes outbreaks.

For such patients, I would suggest that the FDA’s guidelines for a “Compassionate Use Trial” exemption could be modified to include tests of new HSV-2 vaccine candidates that have the potential to serve as “a therapeutic HSV-2 vaccine,” and reduce the symptoms of HSV-2 genital herpes in patients who live with a chronic disease.  The following is one website that discusses the FDA’s Compassionate Use Trial guidelines:  http://www.raps.org/focus-online/news/news-article-view/article/3418/new-fda-draft-guidance-aims-to-clarify-compassionate-use-process.aspx.

The idea of a “Compassionate Use Trial” is that it provides a formal mechanism to request an exemption from the normal FDA policies and procedures to streamline delivery of an Investigational New Drug (IND) to a patient population who (1) could immediately benefit from the new treatment; (2) lack an available medical option to alleviate their symptoms;  and who (3) suffer from a chronic and/or progressive medical condition that is so miserable that they have nothing to lose (and a lot to gain) by enrolling in a clinical trial of a new treatment that may offer some relief.

As I read the current FDA rules and regulations, it appears that “Compassionate Use Trials” only appear to apply to medical conditions that are life-threatening.  I would suggest that the law could (and should) be changed to include any disease that is “chronically and physically debilitating” and for which patients lack any satisfactory treatment options.

I would suggest that many of the HSV-2 vaccines that have been proposed have the potential to serve as “therapeutic vaccines,” which have the potential to re-educate the host immune response to HSV-2 such that it becomes more efficient in its recognition of sites of HSV-2 infection.   In particular, it is well known that the human immune system may, through a variety of mechanisms, become tolerant of foreign antigens.  Thus, it is conceivable that the immune systems of individuals who live with chronic HSV-2 outbreaks may have become “tolerant” of HSV-2’s foreign proteins, and thus it is a selective (HSV-2-specific) defect in their immune response to HSV-2 that explains why they live with chronic herpetic disease.

I cannot offer any proof in support of this hypothesis, but I note that it is an obvious potential explanation for the pattern of infection in people who live with chronic HSV-2 herpes outbreaks, and this possibility could be very simply tested in a “Compassionate Use Trial” in a patient population who have nothing to lose, and a great deal to gain if this hypothesis is correct.

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This post has grown far too long, and so I will stop and leave it here.  The topic of “Compassionate Use Trials” and streamlined delivery of HSV-2 vaccines into Phase I Human Clinical Trials will be a topic that I re-visit in the future.  The bottom line is that I don’t know where the answer lies, but I believe that scientists, regulators, and members of the U.S. Congress need to come together on this issue and figure out a more efficient system for bringing the power of an effective HSV-2 vaccine to bear in a timely manner, so that we may end the HSV-2 genital herpes epidemic sooner rather than later.

– Bill Halford