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The Regulatory Maze: What It Means For Our Health

Doc Gumshoe looks at patents, clinical trials and the path to drug approval and sales

By Michael Jorrin, "Doc Gumshoe", December 19, 2017

[ed. note: Michael Jorrin, who I dubbed “Doc Gumshoe” years ago, is a longtime medical writer (not a doctor) who writes for us a couple times a month about health issues and trends. He does not typically focus on specific investment opportunities, but has agreed to our trading restrictions… as with all of our authors, he chooses his own topics and his words and opinions are his alone]

This will not be a primer about how to maneuver your brilliant idea for a drug that treats a disease for which no treatment currently exists into a successful product that will make billions for you.   No, this will be a general backgrounder, which I hope will help Planet Gumshoe understand the factors that essentially dictate the lay of the land with regard to drugs as well as that vast, amorphous, and growing category of stuff that we lump together under the irritatingly imprecise term, “supplements.”   Part of the reason that we call them supplements is that the term “drugs” is reserved for substances that have been officially recognized as treatment for diseases or medical conditions – in other words, substances that have worked their way through the regulatory maze.   However, many of those substances that we call supplements are really, from the perspective of intention, drugs – that is, they exist for no purpose other than to treat, or at least address, diseases or medical conditions.

An example is a supplement that I took for a couple of years (until I became convinced that it was doing little or nothing), that being glucosamine plus chondroitin.   It is clearly not a nutritional supplement; it’s not that we don’t get enough glucosamine/chondroitin in our diets and therefore need to supplement this deficiency by means of pills.   It is purely and simply meant as a treatment, albeit a palliative treatment, for osteoarthritis.    Is it disqualified from being a drug because it does not address the underlying pathology of osteoarthritis?   No.   In fact, lots of drugs are palliative, including the entire category of pain drugs.   Is it disqualified from being a drug because it just doesn’t work?   Again, not really.   It does seem to deliver some benefit, up to a point, and lots of drugs don’t do much more than that – how many drugs do we know about that are labeled as being “for temporary relief” of this or that condition?   Glucosamine/chondroitin does seem to offer some “temporary relief” of the pain and stiffness of osteoarthritis, at least until the condition gets worse.   So why is it a supplement and not drug?

The answer lies in the regulatory maze.   To be considered a drug, the substance in question needs both to be patented and also to be recognized by the Food and Drug Administration – the FDA (or some comparable authority, such as the European Medicines Agency) – as a drug.   The FDA, by the way, does not grant patents – that’s the province, at least in the US, of the United States Patent Office.

First step into the maze: getting a patent

In the development of a drug, obtaining a patent is the absolute sine qua non and the first step.   If an investigator, whether working for a pharmaceutical company or a university or a medical entity or all alone in his/her own laboratory, comes upon a substance or a procedure that appears to have some promise of actually treating or modifying a disease, a patent application is the earliest priority.   Having a patent application at least in the works is a pre-requisite to publishing a report about the potentially promising new thing, or even to dropping hints about it to your trusted colleague.   Why?   Because news of possible treatment options gets around fast, and the investigator cannot risk having somebody else get there first.   And the planet is well-populated with eager researchers who want to get in on the ground floor of the next big thing.

Not being able to get a patent is a huge obstacle in the development of a drug.   No pharmaceutical company (nor anyone else, for that matter) is going to risk the enormous sums necessary to take a potential drug through the clinical trials necessary to gain FDA approval, unless the candidate drug is patented.   (I am using “FDA approval” to stand for regulatory approval in general, by whatever agency.)   And, by the way, those enormous sums are genuinely enormous – estimates are that it may cost as much as $2.5 billion to fund the entire process.

And, of course, getting a patent on a candidate drug is not by any means a sure thing.   The alternative medicine community’s short take is that no natural substance can be patented.   From this position they move on to increasingly improbable statements, such as that because they cannot be patented, pharmaceutical companies simply overlook the benefits of natural substances, and seek to suppress any information about those benefits, in the interest of keeping patients, and society in general, hooked on their own expensive, sometimes highly harmful, and less effective drugs.

It is certainly true that naturally occurring substances cannot be patented, if what we’re talking about here is a patent on the substance exactly as it occurs in nature.   Oxygen cannot be patented.   But if you were to invent a tiny device that people could carry around in a shirt pocket, and this device was able to separate the oxygen in air from the nitrogen and carbon dioxide, and deliver the purified oxygen to the nostrils via a comfortable little tube, you may be quite sure that such a device could be patented – not the oxygen, but the device that delivers the oxygen.   (Note, there are such devices, but they are big and clunky and not highly portable.)

Or take the bark of the willow tree.   An infusion of this bark, commonly used to treat aches and pains for a couple of millennia, cannot be patented.   But after a chemist isolated the active ingredient and synthesized it, the German drug maker Bayer patented this active ingredient, acetylsalicylic acid, and named it Aspirin.   That was back in 1899.   The patent expired in twenty years or so, but Bayer was able to keep the trademark for a lot longer – long enough to make a fortune.

The same progression, from finding potential benefit in disease treatment in a natural substance, to identifying the ingredient in that substance that delivers the benefit, to synthesizing that ingredient, to obtaining a patent, has been the avenue to development of a huge number of our most successful drugs.   And by “successful” I don’t just mean financially successful, but medically successful.   The drugs whose origins are natural substance include most antibiotics and many drugs used to treat cancer, heart disease, and many others.

So, Dear Readers, when somebody tries to tell you that the reason that pharmaceutical companies are ignoring – and worse, trying to suppress! – the near-miraculous healing powers of this or that natural substance, don’t swallow it.   On the contrary – the pharmaceutical industry is looking extremely carefully at the whole landscape of possible treatment options derived from a natural substance, because that’s where their biggest successes have originated.

But there are obstacles to getting a patent

Patent law is complex, and I can’t claim to understand it in any depth, but the basic requirement for getting a patent on something, whether it’s the drug or the process of making the drug, is that the candidate for patent has to be both new and different.   That seems obvious – there’s no justification in granting a patent to the “same old same old.”   But there are instances in which those requirements can obstruct a patent on a potentially valuable drug.

Suppose a researcher has identified and synthesized a chemical entity that appears likely to trigger a response that effectively rejects invasion by harmful viruses such as those that cause upper respiratory infections – in other words, potentially a cure for the common cold!   That would be a huge breakthrough.   So this researcher submits the documentation to the Patent Office.   The Patent Office investigates the patent application, and finds that some years back another researcher published a paper with much the same information, but did not apply for a patent.   According to its rules, the Patent Office cannot grant a patent to the researcher that applied for the patent, because the candidate is not really new.   The former researcher would have an excellent claim to contest that patent.   So no patent is granted, and the candidate drug will probably not go through clinical trials and reach the market – at any rate, reach the market as a drug.

Or suppose that there is a drug already on the market, but a researcher is fairly sure that it can be improved upon to a significant degree.   The researcher applies for a patent on the improved drug.   But the Patent Office turns down the application on the grounds that the candidate drug is not sufficiently different from the old drug.   The Patent Office is trying to discourage what are known as “me too” drugs, even though sometimes those “me too” drugs represent a genuine improvement over what’s on the market.

The Patent Office does not evaluate drugs and medical devices as to safety and efficacy.   That’s not their job.   What the patent application has to demonstrate is that the candidate drug or device is genuinely novel, that it embodies significant differences from other drugs or devices, and that those differences are not obvious.   Those requirements strike me as reasonable – not especially high barriers to obtaining a patent, and appropriately protective of the investment in time and money by the developer of the candidate drug.

However, this process certainly has the potential to quash the development of potentially valuable drugs.   A supposedly “me too” drug might be different enough from the original to bring substantial benefits to a patient population that did not benefit from the original.

Ways of granting a period during which a non-patented but valuable drug might be protected from competition have been considered.   For example, such a drug might be granted a period of exclusivity, similar to the periods of exclusivity that some FDA-approved drugs have with regard to competition from generic drugs.

You may ask, why should a drug be protected from competition?   Competition, after all, would tend to lower the price of the drug and help the patients who might benefit from the drug.   The answer – you know this already – is that without a guarantee of some time period during which the drug does have exclusivity, no one will risk the money to go through the clinical trials necessary to provide evidence of its usefulness.   And evidence of usefulness is precisely what the FDA requires for a drug to be marketed as a drug in the United States.   Without that evidence, and without going through the long, rigorous, and expensive process of gathering the evidence and presenting it to the FDA, the product – whatever it is – can be sold, but not as a drug.   It cannot be represented as treatment for any disease or medical  condition, whether on the package or in advertising.   A consequence of that regulation is that potentially useful substances are lumped together with the hordes of “supplements” whose benefits are not much more than wishful thinking.

A look at how the FDA approval process works

“Evidence of usefulness” is not the term that the FDA invokes as requirement for approval, but it focuses the mind on the particulars of the process in a way that the more abstract terms – “efficacy and safety” – might not.   “Evidence,” from the Latin rood videre, to see, is information or data that permits us to “see” a proposition or a statement as probably true.   Even though the FDA uses the term “prove safety and efficacy,” evidence is not proof.   The most that can be asserted about any drug is that, based on the evidence, it is probably beneficial in the treatment of medical conditions and diseases.

How do pharmaceutical companies go about assembling the evidence needed to persuade the FDA that their agent should gain approval as a drug?   By means of experiments, called “clinical trials.”   The ultimate goal of these clinical trials is to demonstrate that the candidate agent has some advantage over other agents that address the same disease or condition, whether this advantage is a better outcome for the patient, or a shorter course of treatment, or fewer side effects.   But getting to the clinical trials in which this kind of advantage might be demonstrated is a long way down the road from when the pharmaceutical company first identifies the agent as possibly useful.   Many prior experiments are needed in advance of those human trials.

Initially, these experiments are conducted in the laboratory, to attempt to determine how the candidate agent interacts with other substances.   As they learn more about their agent, the experiments will use animals to try to learn more about the interaction of their agent with living creatures.   Once they have a pretty fair idea that their agent is relatively safe – that is, it didn’t kill the mice – and that it does have some potential for benefit, they progress to experiments with a small number of human subjects.   These tend to be healthy volunteers, and not actual patients with the condition that they ultimately hope to treat.   In these clinical trials, they focus on safety, keep track of any side effects, and track how the agent behaves in the human body – how long it takes to be absorbed, how long it lasts in the body, how it is excreted, what are the likely minimum and maximum dosages.

These are called Phase I trials.   Phase II trials enroll real patients, and try to determine whether the candidate agent has some beneficial effect on the medical condition.   Some of these are “proof of concept” trials and do not go so far as to detect meaningful clinical benefit in patients.   E.g., early trials of PCSK9 inhibitors showed only that blocking that protein resulted in lowering LDL-cholesterol more than previously possible with statins.

Phase II trials are blinded and placebo-controlled, meaning that neither the patients nor the clinicians treating those patients know whether the patients are receiving the actual active drug or a placebo.   Phase II trials are relatively small, a couple of hundred patients at most in total.   They also tend to be fairly short in duration, which means that the outcome measures – the results that tell the investigators whether the experiment is a success or failure – may be indirect.   These indirect results are called “surrogate endpoints.”

A surrogate end point is an easily-assessed measurement of some parameter that stands in for the real clinical goal of the treatment being evaluated.   Employing surrogate end points might be justified on the basis of pure practicality.   For example, a frequent surrogate end point in trials of cancer drugs is measuring tumor size.   If the tumor shrinks, the drug is assumed to be working.   There’s an obvious problem with waiting for the more definitive end point, that being the disappearance of the tumor, or alternatively, the death of the patient.   But tumors have been known to shrink and grow again, so it may be somewhat premature to approve a drug for widespread use based on that particular surrogate end point.

Similarly, lowering blood pressure and lowering cholesterol are surrogate end points for lowering the risk of heart disease, and by and large the evidence is convincing that in patients who are at significant heart disease risk, lowering those parameters does seem to translate into decreased heart disease mortality.   However, we need to remember that for a very long time after cholesterol had been fingered as the culprit in atherosclerosis, all of the experiments to determine whether lowering cholesterol actually conferred a survival benefit were inconclusive – yes, the interventions lowered cholesterol, but it made no difference in patient survival.   It was only in 1994, with the Scandinavian Simvastatin Survival Study, that a clear and definitive survival benefit was seen.   But that survival benefit, quite clear in “at risk” patients, is not so clear in the general population.

Based on the success/failure of the Phase II trials, the pharma outfit may or may not progress to Phase III.   Lots and lots of Phase II trials, by the way, flop, or at least, the results don’t support going ahead with Phase III.   They may actually have negative outcomes, i.e., the candidate drug performed less well than comparable drugs that are already in the market.   There may be troubling safety issues.   Or it may just turn out that the outcome wasn’t promising enough to risk the kind of money that it takes to go ahead to Phase III.

And that is, indeed, a lot of money.   Phase III trials enroll anywhere from several hundred patients to a few thousand, and they cost in the range of $100 million each, and sometimes considerably more.   Results need to be not only statistically significant (not the results of chance) but also clinically meaningful.   Patients in the trial have to demonstrate genuine improvements in their medical condition.   At this point, the pharmaceutical company is looking not only for evidence that will persuade the FDA to approve the candidate drug for marketing, but for the kind of data that bolsters the sales and marketing of the drug.

Issues to consider in planning clinical trials

As the cost of conducting trials escalates, the obstacles become increasingly challenging.   And there are several types of obstacles.   Here are a few:

If it’s a clinical trial of a new drug for a disease for which there are no reasonably effective drugs, patients are likely to be eager to take part – “it’s worth a try.”   But if there are already some fairly effective existing drugs, it’s likely to be difficult to enroll patients in a trial where the patient would not know whether he/she was going to get the existing drug, or a placebo, or a new experimental drug.   Patients newly diagnosed with a disease or disorder want to be treated with a drug that is known to work.

If the trial calls for patients/subjects who have never taken a drug for that disease or condition – drug-naïve patients, as they are known – it may be exceedingly difficult to recruit enough patients for the kind of big Phase III trials the FDA likes to see.

Then there’s the issue of diseases/disorders/conditions that don’t affect large numbers of people.   Again, in such cases, it may be difficult or impossible for drug companies to enroll enough patients for clinical trials.

For those reasons (and others), lots of trials are now being conducted in the so-called “less developed” parts of the world, and sometimes, perhaps, with less rigorous standards than would be expected.

A question that probably puts pharma executives on tenterhooks is whether to conduct trials of their new candidate drug with placebo as a comparator, or to go head to head with an established drug that treats the same disease.   From the marketing standpoint, the big win is to go up against the market leader and do better, at least in some parameters.   The FDA is more likely to grant approval to a drug that is an advance over the current treatment alternatives, and there are several respects in which advantage could be claimed by a candidate drug.   The star would certainly be greater efficacy, which would mean that a higher percentage of enrolled patients met a certain outcome measure with the candidate drug than with the existing drug.   But similar efficacy with fewer side effects would also be a clear advantage.   Other possible advantages could be a longer duration of action, meaning less frequent dosing, or fewer drug-drug interactions, or the ability to treat specific groups of patients who were refractory to existing drugs.

But the thought that haunts them is that they could also lose in such a head-to-head confrontation.   That happens more often than one would imagine.   The pharma outfit confidently launches a Phase III trial based on good solid results in several Phase II trials, and then, to their consternation, they come in second best to the established drug.   I had been working on a physician information package for such a drug, surveying the current treatment options for the target disease, describing the mechanism of action of the candidate drug, and summarizing the earlier clinical trials, when the news that the candidate drug had flopped threw the whole program into a tail spin.   The pharma company then carefully reconsidered its options, weighed launching another Phase III trial, and ultimately decided to shelve the whole thing.   My guess is that by that point they had sunk a huge pile of gold doubloons in the project, and down the drain they went.

Phase IV trials

The research on a drug continues after FDA approval.   Pharma companies will conduct trials of an approved drug in patients with different diseases/conditions, or with versions of the original molecule that are chemically identical but have a different structural orientation, or with the same drug but at different dosages, or with the original drug in combination with another drug.   In some cases, these trials will lead to another patent and also to further FDA approval, resulting in more time during which the drug is protected from generic competition.   Phase IV trials may also investigate safety issues that arose after the original drug’s approval.

How long does all this take?

In some cases, too long – too long, that is, for the pharmaceutical company that developed the drug, and then took it through clinical trials, to make enough money to offset the colossal price tag before the drug’s patent life expires.   Patent life is 20 years from the date of the patent application, which, as you remember, takes place as soon as the drug developer thinks the candidate drug has genuine possibilities.   The clinical trial process, from the earliest Phase I trials through the unblinding of the results of the huge Phase III trials, can easily take 10 years, and in many cases, longer than that.   Which leaves the pharma outfit with perhaps 10 years to recover the costs and start to make a profit.   In the case of drugs that treat diseases/ conditions that affect a lot of people, and for which there is not a great deal of competition, recovering the costs can be accomplished relatively quickly.

But in the case of drugs that treat less common diseases, the earnings can trickle in more slowly.   Some pharmas attempt to compensate for this by setting astronomical prices on their new drugs, to the outrage of patients, insurers, the media, and our elected representatives.   In some cases, they may seek additional periods of “exclusivity” from the FDA, to extend their protected status.   The FDA grants several types of exclusivity, such as:

  • Orphan drug exclusivity, which applies to diseases affecting fewer than 200,000 persons, and runs for seven years from FDA approval, regardless of patent life.
  • New chemical entity exclusivity, which protects the drug from competition from any other drug that includes the same chemical entity as the approved drug.   This exclusivity runs for five years from FDA approval.
  • “Other” exclusivity, based on a report of additional clinical investigation to be conducted after the submission of the New Drug Application (NDA).    “Other” exclusivity runs for three years after FDA approval.
  • Pediatric exclusivity is granted to a candidate drug based on clinical investigation of the candidate drug in children, usually following a request by the FDA for such information.   Pediatric exclusivity runs for 180 days after FDA approval, and may be added to the other three forms of exclusivity.

Exclusivity is granted to drugs to give them additional periods of protection from generic competition.   You may well ask why this is necessary, since patented drugs have 20 years of protection, and if FDA approval is granted in 9 years, the drugs still have 11 years of protection.   Thus, those shorter periods of exclusivity may not really add any protection.   But it may be possible for a competitor drug which is similar, but not chemically identical to the original drug, to be granted a patent, since the rules of the patent office are not the same as those of the FDA.   In that case, the original candidate drug could be protected under the FDA exclusivity provisions after the patent expires.

What about speeding up the time it takes to get drugs to the patients?

Yes, it can also take much too long for a drug to work through the regulatory maze and accomplish its ultimate goal, which is to bestow some genuine benefit on the patients who may have been waiting for relief from their afflictions.   If you remember the early days of the AIDS epidemic, the FDA was roundly chastised for taking way too long to get some of those supposedly promising drugs out to the patients, who needed them immediately if not sooner.   The FDA did initially try to speed up its procedures, but what eventually made a difference was that they instituted some changes in the requirements for approval, specifically for some medical conditions, based on such issues as limited availability of treatment options and urgency of getting some kind of treatment to patients who might have rapidly deteriorating illnesses.

“Breakthrough Therapy Designation,” or BTD 

Here’s a statement directly from the FDA:

“On July 9, 2012 the Food and Drug Administration Safety and Innovation Act (FDASIA) was signed. FDASIA Section 902 provides for a new designation – Breakthrough Therapy Designation.  A breakthrough therapy is a drug:

  • intended alone or in combination with one or more other drugs to treat a serious or life threatening disease or condition and
  • preliminary clinical evidence indicates that the drug may demonstrate substantial improvement over existing therapies on one or more clinically significant endpoints, such as substantial treatment effects observed early in clinical development.

If a drug is designated as breakthrough therapy, FDA will expedite the development and review of such drug.  All requests for breakthrough therapy designation will be reviewed within 60 days of receipt, and FDA will either grant or deny the request.”

At this point, the FDA has received 501 request for breakthrough therapy designation and approved 180, a 36% hit rate.   So BTD has somewhat speeded up the time it takes for drugs to get to patients, for some drugs.

But the FDA also gets criticized, sometimes, for being a bit too lax.

A JAMA paper (Downing NS JAMA 2014;311(4):368-377) examined the basis on which new drug treatments were approved by the FDA between 2005 and 2012.   A total of 188 new drugs were approved, for 206 indications.   These approvals were based on 448 so-called “pivotal” trials, meaning relatively large Phase III trials.   However, the investigators reported several findings of concern:

  • Of the 188 new drug approvals, 74 were based on the results of a single pivotal trial.
  • 91 – almost half – were based on surrogate end points rather than on clinical evidence of improvement in the patients’ disease or disorder.   Only 67 were based on actual clinical outcomes.
  • Only about 40% of the trials compared the new agent with an existing drug the rest compared the new agent only with placebo.

Granting approval to a drug based on a single trial might be justified based on the importance of making the drug available to patients for whom other options are significantly less effective, or if there are impediments in mounting another large Phase III trial – i.e., difficulty in recruiting patients.   However, a fundamental scientific principle is that results of experiments – and a clinical trial is definitely an experiment – have got to be able to be replicated.

It’s clear that there is an inherent tension between the need for more evidence and the need to get drugs to patients as quickly as possible, and it’s also clear that the FDA falls short of perfection on both counts.   But the FDA process, with all its flaws, is representative of the difference between science and magic, or between chemistry and alchemy.   David Wooton, in The Invention of Science, says:

“What killed alchemy was the insistence that experiments must be openly reported in publications which presented a clear account of what had happened, and they must then be replicated, preferably before independent witnesses.   The alchemists had pursued a secret learning, convinced that only a few were fit to have knowledge of divine secrets, and that the social order would collapse if gold ceased to be in short supply.”

The regulatory maze has largely shaped the entire pharmaceutical industry.   Without the strictures of the patent office and the FDA, and their counterparts elsewhere on the planet, there would have been an enormous temptation for drug makers to develop their products in the strictest secrecy, like the alchemists of old.   They could have developed drugs and simply put labels on them that claimed all manner of benefits and cures.   In fact, before the dawn of government regulation of drugs, that’s exactly what they did.   It was then up to the public – doctors and patients – to pick and choose among these drugs.   Some of those drugs worked pretty well and some were frauds.   The word might eventually get out as to which were which.   But the drug makers didn’t have to launch expensive clinical trials and wait years before starting to make serious money.

Relations between the FDA and the pharmaceutical industry have sometimes been contentious, and the regulatory maze has hugely increased the cost of drug development, but on balance, regulation has resulted in a benefit to the commonwealth .   Drug makers can put their products before the medical community and their patients with the imprimatur of a powerful government agency, and patients can use these drugs with a degree of assurance that they will work and do no serious harm.

* * * * * * *

I hope that readers can detect that I am being guarded in my praise for the work of the regulators.   It’s evident that the FDA approves drugs that are later found to cause significant adverse events, and that the efficacy of some FDA-approved drugs is not what was expected.   Sometimes the FDA approves drugs that, in my opinion, should have been rejected, such as flibanserin (Addyi), aka “Viagra for women.”   Most of the time, however, the FDA tries to strike a reasonable balance between optimism and caution.   The drug developer presents evidence, vast amounts of it, but also casts the evidence in the most positive light.   The FDA balances pressure from several quarters – the pharma industry, of course, but also medical societies and patient advocacy groups.   And the FDA acknowledges that the ultimate responsibility lies with the treating physician, who has to be sure that the benefit from the drug outweighs the risk of drug-related adverse events.   If the patient has a potentially fatal cancer, it’s probably worth taking a larger risk than if the condition to be treated is hay fever, for example; thus, hay fever drugs that could (rarely) cause a potentially fatal heart arrhythmia were taken off the market.

The benefits of regulation are overwhelmingly evident from population data.   We’re living longer, and we’re managing most diseases much better than we were before drugs had to negotiate the regulatory maze.   The current system is far from perfect, but it’s an improvement over what prevailed in the unregulated days of yore.




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5 years ago

Michael – Another terrific article! Thank you very much…a great read; interesting and informative.