Thursday, September 20, 2012

How drugs are made / why it takes so long?

Motivated patients can often get the scoop on an exciting drug very early in a drugs lifecycle.  Occasionally, a drug is obviously effective in early testing yet it can be 5-6 years before the therapy is available to the general public.  I’ve seen patients post their results to the web and entire groups of patients may know about the success or failure of a drug even before the company conducting the study is aware.  When someone is running out of good options the delay between drug creation and drug marketing can feel like an eternity.

So why does it take so long?  It is probably not what you think (in fact the FDA may be one of the faster elements of the process).  Once a molecule is patented, the clock is ticking on how long a company can make a profit on a drug.  Furthermore, companies have a daily “burn rate” which is the cost of keeping their company going.  Conducting scientific experiments is extremely expensive.  Without a product on the market, a small biotech company can get very anxious to move the process as quickly as possible – but data takes time to create.  For bigger companies the daily cost of operations is truly enormous.  They may have more flexibility than a smaller company but bad management, failed late stage studies, and thin pipelines has doomed even some of the biggest companies.

A drug is typically born when a lab scientist working at a pharma or biotech company designs some sort of experiment then screens a range of compounds to see if they can change the result of the experiment in some desired way.  This process isn’t really a discrete step in the process.   There may be a lot of back and forth with compounds that are selected, refined, modified, thrown out, started over, discarded again, re-modified, etc.  Depending on the complexity of the experiment (assay) or number of experiments this can take many months to even years.  Larger companies have introduced automation to the process and “compound libraries” which may literally have tens of thousands of potential drug molecules can be screened very quickly.

Once a compound is identified that accomplishes some biochemical task, it is carefully analyzed to determine if it has pharmacologic properties that make it likely to be a decent drug.   Medicinal chemists may then make any number of modifications to the original molecule to “optimize” it for drug delivery.    Not every drug does a good job dissolving where it is supposed to dissolve, get absorbed where it is supposed to be absorbed, last long in the blood, etc.  Depending on how the process goes, that may punt it back to the prior step a few times.

Once a drug is selected and optimized there may still be a year or more of work to do before it can ever get close to a human study.  It has to be run through a ton of safety screening studies – does this affect cardiac conduction, mutate DNA, alter effects of metabolism in the liver of other drugs etc.  Only after all that is done, a company has to do animal studies mandated by the FDA.  Usually this includes both 28 day safety and longer in rats and two mammal species like mice, dogs, or monkeys. There are a lot of regulations about this sort of testing so it cannot be casually done. Because this step can be so expensive, smaller companies may spend a lot of time on prior steps to make sure the molecule is exactly what they want before doing these sorts of studies.

Once all that is done, the company can go to the FDA and register for an “investigational new drug.”  Once an IND is granted it allows them to conduct the first human experiment so there is a lot of data review at this point.

Companies may have a lot of talent in house to do a lot of things, but most companies do not have “thought leader” level expertise in any particular disease.  At this point there may be a lot of discussions with academic opinion experts, meetings called “scientific advisory boards” to help educate the company about specifics of trial design, disease features, etc. 

I do need to editorialize here for a moment.  In the past, there have been abuses between pharma and physicians.  Docs were given expense paid trips to attend “advisory boards” which were thinly veiled commercials for products.  These were excessive and wrong.  I am glad they are gone.  New policies make it required to disclose all payments from pharma to physicians.   Unfortunately one bystander effect of the regulations and policies has been to stifle the critical communication that needs to be exchanged at this step of drug development.  An increasing number of high level thought leaders are no longer sharing their expertise in these environments for concern of being mischaracterized as “in the pocket” of pharma for receiving a payment that often does not even cover the expense of being out of clinic.  Oh well, such is the cost of our good intentions – back to drug development.

The first step in clinical development is typically a phase I study.  In this sort of study, small groups of patients are given the therapy for a duration of time and closely followed for safety.  If they do well, another group is given the treatment at a higher dose and so forth.  An individual cohort may take a few weeks to a few months to fill with patients.  Often patients are followed for a month.  Following each dose period, there is typically a conference call to address safety.  “Herding cats” hardly does justice to the attempt to get 6-8 research physicians onto a single conference call.  Therefore a single dose cohort often takes between 6-8 weeks in ideal circumstances.   

The purpose of phase I studies is to define “maximum tolerated dose.”  Fortunately / unfortunately many of the new precision drugs have far less side effects.  As a result you can find yourself testing doses far higher than you actually need.  There is always a lot of hand wringing about defining the “RP2D” aka: recommended phase two dose.  I treated the very first two CLL patients in the world with ibutinib.  It was clear within 24 hours that we had something very unique.  Lymph nodes were smaller, WBC shot up, patients felt good, etc.  That was back in 2009 (If I recall correctly).  We are still a ways off from FDA approval despite the clamoring of many patients to get access to the drug.

Once RP2D is established, companies start phase II testing.  Perhaps they got some hints from phase I about certain types of patients they want to evaluate.  Between settling on study design, site selection, IRB approval, contract approval, etc it may take over a year to launch a phase II study and get “FPI” aka: first patient in.  The major academic universities and cooperative research groups recently launched a major initiative to ensure they could meet the one year deadline – pretty sad as far as I am concerned.  My group targets 6 months for phase II/III testing and 3 for phase I studies.  In most cases that trounces the competition.

Patient accrual to studies is often painfully slow.  Often a site commits to 0.3 patients per month in lymphoid studies (4 patients in a year) because a specific population is desired.  Imagine how many sites are required then to execute a 60-120 patient study in a timely manner. 

You also have to think about the purpose of phase II testing which is really about exploration of efficacy.  At the end of a phase II study, you want to have the data you need to design the right phase III study which is typically the basis for drug approval (for many drugs in fact – two positive phase III studies are required).  You typically want to identify the best patient subgroup (prior therapy, molecular details, medical comorbidities etc.).  Not only do you need mature data, you need to make sure the data is clean (there is an entire industry called CRO / contract research organization to assist pharma companies ensure that their data is accurate) and then analyze it.  You may need 2-3 years from phase II FPI to have a good grasp of your drug.  Remember – response rate is the fastest variable to measure, but rarely indicative of true activity of a drug.  Instead, you often need PFS (progression free survival).

During phase II testing, the clamor for a new drug can begin to get very strong.  Often several phase II studies are ongoing at same time and several hundred patients have had access to the drug.  Data has been presented at major conferences and “the word is out.”  RARELY- FDA may approve a drug on the basis of very compelling phase II data.  By FDA standards, approval from phase II requires that a patient have received ALL PRIOR APPROVED THERAPIES for an indication and need new treatment (ie. unmet medical need).  Don’t expect too much logic here – sometimes things just don’t make sense.  Why would ofatumumab not be approved in bulky CLL (where campath does not work) unless patient had prior campath….

Trying to get approval out of phase II is a very valuable shortcut for pharma but becoming very difficult in CLL/NHL. This is where “companion diagnostics” are becoming increasingly valuable.  If you have a test that predicts exactly which patients are likely to respond and which are not – FDA may allow faster passage (eg. Xalkori in lung cancer).

Often small biotechs with successful drugs are swiped up by larger pharma when a drug appears promising.  Just count on a 6 month productivity wipe-out as the two companies merge and figure out who makes what decisions.

Finally, 2-5 years after a drug entered human testing you are probably ready for phase III testing.  Bring all the same baggage from before (thought leaders / protocol design, study start up times, etc.)  Now set out to prove that your treatment helps people live longer than prior therapies.  In CLL where front line therapy may be associated with remissions that may last 6 years or longer – not to mention salvage treatment!  Aargh.  How are you ever supposed to get a drug approved.

Fortunately there is such a thing as “surrogate end points.”  These are clinical variables that the FDA may accept instead of overall survival in studies with such long natural histories.  The slope is ALWAYS slippery here.  Ideally you meet with the FDA beforehand and work out a “SPA” or special protocol assessment.  This essentially is a promise that if you meet a certain endpoint, you can get your drug approved.  Sometimes there can be some “gray territory” between what is a promised endpoint and what is a suggestion.  Quite a few times a company has crossed the finish line and found out that the finish line actually moved….

Phase III testing is a gamblers paradise.  There are so many ways a trial can fail that it is amazing anything succeeds.  Credit belongs to the determination of many individuals who make the science happen.  With single studies often costing tens of millions of dollars to execute – this gets to be really high stakes.

Keep in mind patients are often appropriately  clamoring for “compassionate use” at this point - yet every patient who gets the drug outside of a study could very well be one patient that might have been accrued to the study if they were able to make it to a study center.

Finally after one (or ideally two) successful phase III studies (by which time, estimates are that that a company may have spent $800 million dollars on a drug) you can take your drug to the FDA.  You package up all of your data and file an NDA (new drug application).  FDA appropriately scrutinizes this data extremely closely.  Sometimes individual patients are thrown out (despite the cost of 20k it took to get their data).   FDA is usually able to turn around a decision in 6 months.

Once approval is granted – you have a drug you can sell.  Cost is another conversation all together and I cannot possibly touch that in this post (fingers cramping already).  As you can see – this is a very slow science.  For patients facing a fatal disease it can feel unfair.  I’ve had drugs in my pharmacy that might be significantly life prolonging for a patient who is dying, but cannot give it to them because they are ineligible for the study.   It is hard on me too – but one of those no-no’s you would NEVER do as a research doc as you would be swiftly banned from research if you were to do so.

Emotions run high in the process.  Most of the people I know in research truly want to do it for the benefit of the patients.  I often hear comments about sinister influences on the process but I think most of the time those are more based on ignorance than reality.  Of course companies wish to have a profit at the end of all this.  Who can blame them?  Would you give away hundreds of millions of dollars purely out of altruism?  Perhaps some would, but it wouldn’t look like the research pipeline we have today.

I believe chemotherapy will be obsolete for most patients with CLL within 5-10 years.  After that, I think only a small minority of patients with the disease will die from it.  For NHL, the biology is a little more complicated.  Thus far the targeted treatments have not been as robust, but there are still significant advances being made today.  I hope everyone can take a deep breath and find their way to a center that offers research.  It will speed things up for all of us!