Studies compared mice born and kept in a sterile environment with no bacteria in their gut against mice born and kept in a non-sterile environment.  Both sets of mice were fed the same amount of food.  The bacteria-free mice stayed skinny while the mice with gut bacteria gained weight.  The reason is that the bacteria in the intestines of the mice raised in a non-sterile environment were able to break down the food and turn it into calories, while the food passed right through the intestines of the bacteria-free mice undigested.

These findings beg the question: can we manipulate the bacteria in our intestines in order to control weight gain or loss?  For more information on the research and its implications, check out the printed article on the NPR website here.

The eCTD is a specification designed by the International Conference on Harmonization (ICH) to provide an interface for pharmaceutical companies to transfer regulatory information (such as marketing applications, renewals, variations, etc.) to health authorities.  The eCTD specification consists of five modules: 

1. Administrative Information and Prescribing Information
2. Common Technical Document Summaries
3. Quality
4. Nonclinical Study Reports
5. Clinical Study Reports 

Module 1 is regional in nature, and the requirements and structure of this module varies from country to country.  Modules 2-5 are the same for all countries that adhere to the specification. 

An application for marketing authorization may consist of hundreds to thousands of distinct documents (chemistry, manufacturing and control (CMC) information, benefit/risk analyses, labeling, study reports, etc.).  The eCTD specification outlines the types of files that are supported (PDF, RTF, JPEG, etc.), folder structure requirements, naming conventions for files and folders, metadata requirements (such as a table of contents) and stylesheet guidelines.  A submission that is structured according to the specification can be viewed using an eCTD viewer or even a standard web browser. 

The ICH consists of representatives from the big three regulatory bodies (US, Europe and Japan). So, of course, these agencies are leading the way toward fully electronic interfaces. 

• As of January 1, 2008, all marketing applications must be submitted in eCTD format to the FDA. Waivers are available by request.
• From July 1, 2009, the EMEA will strongly recommend eCTD format submissions for all approval routes. Exceptions may be granted by request.
• Japan’s authority (MHLW) accepts eCTD submissions, but adoption has been slow due to unique MHLW requirements for Module 1. 

Some other countries, such as Australia and Canada, have also taken steps toward eCTD requirements. 

The goal of the move to electronic submissions is to decrease the amount of time it takes for the health authority to review an application and its related lifecycle documents.  However, after the first six months of the FDA’s 01-Jan-2008 mandate, results were mixed (see “The eCTD - a Six-Month Checkup” on Bio-IT World.com).  The FDA received over 30,000 electronic submissions in the first six months, but many submissions were of poor quality (e.g. missing table of contents, missing Module 1).  These mistakes often result in application rejection, which in turn, ends up increasing the amount of time for review.  

Things are expected to get better, though.  The pharmaceutical companies will get better at electronic submissions (either through building skills in-house or outsourcing) and the tools for authoring eCTD-compliant repositories and managing changes to the application throughout its lifecycle will improve.  Electronic submissions are obviously a vast improvement over paper submissions on all fronts.  There will be growing pains, but we should see significant positive results before the end of the decade.

In today’s healthcare environment, with the internet and media coverage providing early stage insight into developmental pipelines, more and more physicians and patients are calling for access to drugs before they are approved for marketing.  However, it’s not always the FDA that stands in the way.  The drug companies also have to agree to provide their developmental products for special access. For various reasons, they are not always willing to do it. 

The treatment of a seriously ill patient with an unapproved drug is often referred to as “compassionate use”.  The FDA has had regulations in place for the compassionate use of drugs since 1987.  In the U.S., when a patient is not able to enroll in a manufacturer-sponsored clinical trial, the patient has two options to obtain access to an investigational product: (1) an expanded access program or (2) single patient access by special/compassionate exemption. 

With an expanded access program (EAP), the sponsor (the drug manufacturer or a health organization such as the National Cancer Institute) must apply to the FDA to provide special access to a group of patients.  The EAP is conducted as a research protocol in a clinical setting such as a doctor’s office or university research facility.  This type of program is typically offered in the later stages of clinical trials when the safety and efficacy of the product have been fairly well established.  In addition, an EAP works well when the patients live in the same general area near the research facility.

If no EAP is offered by the sponsor (e.g. for drugs used to treat rare diseases) or the patient is not eligible for an EAP due to program criteria, location or other factors, then the patient’s physician may apply for a special exemption.  First, the doctor must get the drug company on board. Then, the doctor, with assistance from the drug company, applies to the FDA for authorization to provide the drug to the patient.

The FDA states that it rarely blocks access to unproven medications for those with serious illness; however, it does reserve the right to reject applications for special access when it feels that the drug is not safe (even if the patient is already dying).  While the FDA does sometimes reject requests for compassionate use, it is often the drug manufacturers that withhold their products.  Compassionate use programs can be very expensive and time-consuming.  The companies are under no legal obligation to provide access to the drugs, and the FDA has no authority to compel the pharmas to offer EAP’s or single patient access. 

Some of the reasons that a drug company may choose not to offer a compassionate use program are:  

• The company’s ultimate goal is to get the product approved for marketing. Compassionate use programs divert time and resources away from achieving this goal.
• Compassionate use regulations can be complex and different from country to country. The regulatory affairs department must be prepared to wrestle with these regulations or the company must pay an outside vendor to deal with the health authorities.
• The company must take on additional costs to manufacture, distribute and track the product.
• The company must perform pharmacovigilance in order to monitor the products safety and efficacy as well as track, assess and report adverse events.
• These programs cannot be promotional in any way. Companies are not able to solicit patients and physicians without heavy fines.
• The drug is often offered free-of-charge to the patients as part of the program. Thus, there may not be any money coming in to recoup the costs of the program.
• In the end, the product may not be approved. Why go above and beyond the clinical trials that are already required?

On the other hand, drug companies are starting to realize that compassionate use programs provide a number of benefits.  First and foremost, these programs help patients that are in desperate need for treatment.  This should be priority #1 for drug manufacturers.  Other benefits include: 

• If the manufacturer does not provide access to product, patients may use other means to get their hands on it. These programs give manufacturers tighter control over the patient population and the distribution network.
• While these programs are not a replacement for clinical trials, they provide additional real-world safety data over clinical trials alone.
• The programs allow a company to get into a market earlier than usual. The patients that participate in the program remain patients (customers) after the product goes to market.
• Physicians and opinion leaders get involved earlier in the development process. They become the initial adopters that build industry confidence in the product and accelerate growth once the product is approved. This is especially important in countries where the manufacturer may not have existing relationships within the healthcare arena.
• The company will have a better idea how to market the product. It will have a more complete understanding of the customers and their needs.

While the public perception is that the FDA restricts access to experimental products, the arguments above contend that this is not always the case.  The FDA has provided a framework for compassionate use programs, but this framework relies on the willingness of drug companies to provide access to their drugs.  And unfortunately, the reward of compassionate use programs often does not always outweigh the risk. Perhaps more incentives are needed? Or streamlined processes around compassionate use programs? 

What do you think?  Your thoughts are welcome.

There are a number of strategies that the brand-name manufacturers have employed since the Hatch-Waxman Act in 1984 in order to stave off generic manufacturers and retain market exclusivity.  The most common tactic is a combination of “evergreening” and aggressive litigation.  With evergreening, the company stockpiles patents on as many aspects of the product as possible.  When a generic company attempts to get marketing authorization, the brand-name manufacturer takes the generic company to court over claimed infringements with some patented aspect of the product.  This allows the drug manufacturer to delay the entry of competition and retain its big profits (for up to 30 months or longer in the U.S.).

However, litigation is only a short-term strategy - eventually the generic drug makers will enter the market.  Other tactics meant to invoke a more gentle decrease in product price once the generics invade are: 

• Patents on new formulations / combinations - Coming up with better delivery methods, simpler administration routes (e.g. once a day versus three times a day), combination products and new isometric forms may stifle competition and keep doctors and patients coming back to the brand name
• Patents on improvements in the manufacturing process in order to decrease costs
• Aggressive advertising campaigns to keep their products fresh in the minds of doctors and patients. In addition, brand-name manufacturers jump on every opportunity to promote bad press about unexpected adverse events with generics (i.e. the heparin from China fiasco) or poor manufacturing controls (such as the FDA ban of 30 generics from Ranbaxy). These negative advertising campaigns are meant to scare consumers aware from generics.

Lately though, the market is starting to take a different turn. In a number of ways, the brand-name manufacturers are starting to play more of a hand in the generics market. 

• Some brand-name manufacturers have begun marketing their own “authorized generic” to compete with the first generic manufacturer to gain entry. This may be done through a subsidiary or through a licensing deal with another generic manufacturer. The brand-name manufacturer gets a slice of the pie while decreasing the profits for the first generic competitor. When paired with the delays and costs of an aggressive litigation campaign from the brand-name company, the generic drug maker may be deterred from entering the market at all.
• A number of big pharmas have started purchasing generic companies. This serves three purposes: (1) it allows the brand-name company to launch their own “authorized generics” through a subsidiary that is better suited for the generic business, (2) it enables brand-name manufacturers to have a presence in countries that cannot yet afford brand-name prices - such as Brazil - and (3) it decreases competition, allowing prices and profits to remain higher. This has started a domino effect as big generic companies are forced respond in kind - case in point: Teva’s recent purchase of Barr Pharmaceuticals.
• In some recent cases, the brand-name manufacturer has resorted to financial arrangements - or what some may call payoffs - in order to stifle competition. For example, see Pfizer’s settlement with Ranbaxy to delay their generic version of Lipitor by 20 months. While these arrangements may violate antitrust laws, the government has not levied any punishments yet.

So while the percentage of drug prescriptions dispensed for generics has steadily increased over recent years, the brand-name manufacturers have been able to keep their percentage of sales fairly high (84% in 2007, down from 88% in 1999).  Surely, this battle will continue to rage on for years to come. Hopefully, the generic industry will be strong enough to keep prices affordable for consumers, while the brand-name drug makers get enough market share to continue to bring innovative products to patients. Balance will be the key.

Can you guess which agency granted approval and which agency did not?  If you’ve been following the pharmaceutical industry for the past five years or so, then you probably guessed that Bridion was approved by the European Commission (EC) and turned down by the FDA.  And you’d be right.  This isn’t the first time that the FDA has rejected a product that was approved in Europe, but the fact that all signs were pointing toward approval and the fact that the FDA rejected Bridion a mere three days after it was authorized by the EC, makes it a stand-out example of just how cautious the FDA has become.

So why was it a surprise that the FDA rejected Bridion? 

First, Bridion (or sugammadex by its generic name) is seen by many as a breakthrough drug in the anesthesia field.  Its manufacturer, Schering-Plough, states that “it was specifically designed to reverse within minutes both moderate and deep muscle relaxation induced by rocuronium or vecuronium during general anesthesia. As a result, BRIDION can give anesthesiologists greater control in managing the depth of muscle relaxation through to the end of a surgical procedure.”  The drug is able to quickly reduce paralysis induced by anesthesia, allowing doctors to take the patients off breathing tubes in less time and reduce the side effects of being “under” for a long duration, such as undetected loss of oxygen.  In clinical trials, Bridion showed an ability to reverse muscle relaxation with a median time under 3 minutes, up to 9 to 12 times faster than neostigmine with glycopyrrolate.

Second, the safety risks had not raised any eyebrows during clinical trials.  The most commonly reported adverse effect was a metallic or bitter taste.  Some patients experienced anesthetic complications, such as limb movement or coughing during surgery, or unwanted awareness during anesthesia. Other patients experienced allergic reactions, but these reactions did not appear to be any worse than the reactions caused by the most commonly used anesthesia drugs today - neostigmine and succinylcholine.  In many physicians’ views, the benefits of faster paralysis reversal far outweighed these safety risks.  In fact, the advisory committees for both the FDA and EC performed their respective benefit/risk analyses and gave their recommendations for marketing approval.

Regardless, on August 1, 2008, the FDA rejected Bridion citing concerns about “hypersensitivity and allergic reactions” to the drug.  The agency raised no concerns about the drug’s effectiveness. Meanwhile, the first post-marketing patient was treated with Bridion in Sweden last week. The physician reported that the patient experienced reversal from the muscle relaxant used during surgery in just two minutes.

Schering-Plough plans to move forward with its plan to market the product in the U.S., and perhaps the authorization will go a little smoother after the FDA allows the Europeans to be their test subjects for a little while.  Maybe the U.S. will see Bridion soon… or maybe not.  We’ll have to wait and see.

TA-CD essentially works just like vaccines that are used to fight traditional diseases (such as tetanus or the mumps). It gets the body to recognize cocaine as an invader and uses the body’s immune system to prevent the cocaine from doing what it normally does: get the user high. 

As we know, the body doesn’t normally treat cocaine as a harmful trespasser, so TA-CD pairs deactivated cocaine molecules (norcocaine) with deactivated cholera toxin molecules.  The body recognizes cholera as an enemy, and since it is paired with cocaine molecules, the body builds anti-bodies to fight both foreign substances.  The anti-bodies bind to the cocaine molecules, and the resulting bound molecules become too large to enter the user’s brain.  As a result, the patient does not feel the high associated with cocaine use.  In other words, the patient builds immunity to cocaine.

Celtic reports that it completed four Phase II trials with 161 patients prior to 2007 and a larger Phase II trial was slated for 2007.  Preliminary results from the Phase II trials showed efficacy (an increase in cocaine-free days) in a significant number of patients in the treatment group (see the article in Medical News Today for more information).

Of course, Celtic does not plan to lobby to get TA-CD introduced into the list of common childhood vaccinations just yet.  They intend to market the product to assist in the fight against cocaine addiction.  Celtic reports that 800,000 patients in the US attend in-patient programs and out-patient clinics seeking treatment for cocaine addiction, and more than 95% of all cocaine addicts who try to quit relapse.  This is a significant patient population that can benefit from this product.  Along with counseling and the support of family and friends, it will be a tool to help addicts quit. 

Further back in Celtic’s pipeline is TA-NIC, a nicotine vaccine.  If TA-CD is successful, it may pave the way for TA-NIC as well.  It’s not hard to imagine a full suite of vaccines against our pharmacological vices (marijuana, MDMA, heroin, crystal meth, etc.) on the market some day.

I’ll be looking for answers to some of the following questions in the Phase III studies: 

• How long will the vaccine last before a booster dose is needed?
• How many patients will overdose because they increase their cocaine intake in hopes of overwhelming the anti-bodies and getting their high?
• How many patients will switch to another drug (e.g. methamphetamines) to get their fix?

And if the product makes it to market, how will our society react? 

• Will addicts really submit to the vaccinations if the product promises to kill their high for, say, 10 years like a tetanus shot? That’s a big commitment for an addict - there’s no turning back.
• Will parents vaccinate their children against cocaine?
• Will employers require their employees to be vaccinated?
• How will cocaine producers innovate in order to retain their business?

This is an interesting product to keep an eye on.  Your thoughts and comments are welcome.

There was one registration status in the database that was specific to the FDA and struck me as somewhat odd: “approvable”. At first, I wondered if “approvable” was even a real word. Looking it up in the dictionary, I found that it meant “capable of being approved.” So, I asked myself the following question: if a drug is capable of being approved, why wouldn’t the FDA just approve it? I found solace in the fact that I was not the only one confused by this term - much of the industry was also puzzled as to its meaning.

On August 11, 2008, a new FDA policy went into effect that removed the term “approvable” from the FDA drug review process. The remainder of this article reviews the changes and the impact to the industry.

The FDA’s Drug Review Process - Then and Now

When the FDA receives a New Drug Application (NDA), it has 60 days to perform an initial review and determine if the application is worth moving to a full review. If the application is incomplete (e.g. required studies were not performed), the FDA will reject it.

Prior to August 11, 2008, there were three possible outcomes of the full application review for accepted submissions:

• an “approval” letter, meaning the drug has met agency standards for safety and efficacy and the drug can be marketed for sale in the United States
• an “approvable” letter, meaning that the drug can probably be approved, provided that some issues are resolved first
• or a “not approvable” letter, meaning that deficiencies are significant enough that it is not clear that approval can be obtained in the future, at least not without substantial additional data

The FDA would issue an “approvable” letter for any number of reasons, from small modifications such as changes to the labeling to large undertakings such as additional clinical trials. The majority of “approvable” drugs eventually go on to win approval. However, in a number of cases, the changes required for approval were too expensive or time consuming for the sponsor, and the project was killed.

With the new policy, there are now two possible outcomes of the full application review:

• an “approval” letter
• or a “complete response” letter, meaning that there are deficiencies in the application such that the application cannot be approved in its present form

The Intent of the New Policy

The FDA’s stated intent behind the change is two-fold:

• Consistency - The FDA has been using “complete response” letters in lieu of “approvable” and “not approvable” letters in the Biologics License Application (BLA) review process for some time. This change brings the NDA review process in line with the BLA process.
• Neutrality - The FDA no longer wishes to imply whether or not a drug is eventually approvable; instead, it only wishes to inform the sponsor of the changes that are required for approval.

The Impact of the New Policy

The most notable difference is the discontinuation of the “not approvable” letter. In the old policy, the “not approvable” letter was effectively a rejection letter - not in all cases, but most. To investors, it was fairly clear that the drug was not going to make it to market, and the stock price of the sponsor company would fall accordingly. The sponsor’s hands became tied as Wall Street had already made the decision as to the future of the drug.

Since the content of a “complete response” letter, as with the old “approvable” letters, is proprietary to the sponsor, it will be more difficult for investors to immediately determine how close a drug is to approval or, conversely, application withdrawal by the sponsor. This is good for pharmaceutical companies. In case of bad news, they will have more time to do damage control before the content of the FDA’s response is known.

However, in the end, the “complete response” letter is not much different than an “approvable” letter. The “complete response” letter still leaves the drug company in limbo as to the future of the product. How much more money must be spent for approval? How much patent time will be lost? Will the product be able to recover the cost and effort necessary for approval?

Since the year 2000, the number of “approvable” letters issued by the FDA has been on a steady rise. The FDA issued 35 “approvable” letters from 2001 to 2004, 13 in 2006, and 23 from Jan 2007 - Sep 2007 (see the “FDA’s Approvable Problem” from Pharmaceutical Executive magazine). There are a number of theories as to why this increase has occurred, but regardless, it is a real phenomenon that is costing sponsors money and killing potentially useful drugs.

In the eyes of the pharmaceutical companies, real change will only come if the FDA reduces the number of “complete response” letters that it sends and increases the number of “approval” letters for first-time submissions. It is doubtful that this will happen anytime soon, but we’ll have to wait and see.

The kicker is that ROXRO has only six employees. Six employees?!?!  Did I hear that correctly? How does a company with six employees get a drug through Phase III trials and on the doorstep of marketing approval?  Doesn’t it take a small army of people to get a drug to market in the United States of America?  I decided to dig a little deeper and find out how they do it.

ROXRO states that it was one of the first pharmaceutical start-ups built upon the “virtual company” business model.  They operate under a highly experienced senior management team with little to no administrative or professional staff.  Since they have only a small number of employees, there are almost no infrastructure costs.  There’s no need for a HR department, or an IT team or a Finance division.  There’s no need for a company headquarters.  Communication is done through cell phone and email.  Documents are shared via an online file storage site.

OK, but what about the drug development process?  How do they do it with six executives?  First of all, ROXRO is not in the business of trying out thousands of compounds in order to discover a new chemical entity.  They leave that type of work to the big pharmas.  Instead, ROXRO in-licenses promising drug candidates for rapid development in acute medical conditions.  They engage their scientific advisors and a global network of external experts in academia and other small pharmas or biotechs to find and acquire discarded or failed drugs that still have marketing potential.  Then, they figure out how to tweak the product so that it can be successful.

In the case of ROX-888, ROXRO took Ketolorac, a well-known molecule for the treatment of acute pain, investigated why it didn’t work in an oral dosage, and saw the potential for it to be successful in an intranasal form.  Then, they outsourced the drug development, manufacturing and clinical trial programs to external vendors.

Of course, ROXRO needed money to do all of this.  Investors were willing to invest for a number of reasons: ROXRO’s experienced management team and network of experts in the therapeutic area (pain management), their low overhead costs due to their virtual model and the ability to keep their risk profile low by acquiring known - albeit failed - drugs for a more rapid progression through the clinical process.

The final piece of the puzzle is to find a partner (or buyer) in big pharma that has the pocket book and the resources (e.g. employees) to get the drug to market and keep it there.  ROXRO’s plan is to stay small and let the partner handle the resource-intensive operations such as sales & marketing, regulatory affairs, pharmacovigilance, manufacturing, legal, etc.  At present time, ROXRO is seeking U.S. partners for ROX-888.

So, that’s how it’s done.  If you are a scientist with a great drug product idea but think that you do not have the means to get your product to market, perhaps you should think again.  Start up a virtual pharmaceutical company with a few of your experienced and motivated colleagues, get some venture capital, outsource the development and clinical trials, find a big pharma partner, and the next thing you know, you’ve got a product in the game.  Piece of cake, right?

One of the persistent challenges of the Pharmaceutical industry has been maintaining the safety and efficacy of drug products in patients over time. In other words, when a patient starts taking the drug, the patient is able to take a lower, safer dose of the product in order to treat the symptoms. However, over time, the patient becomes desensitized or builds tolerance to the drug such that he/she must take higher, less safe doses of the product in order get the desired effect. Eventually, the dosing may reach dangerous levels causing serious, or even fatal, side effects. The crux of the problem is that the pharmaceutical industry does not really have a handle on how target drug-receptors are activated or de-activated in the body in order to achieve the desired result. As a result, desensitization is viewed as an unavoidable side effect.

Last week, I attended the NYC Bio Meetup. One of the presenters was Richard G. Lanzara, President of Enhanced Pharmaceuticals (EP). EP is attempting to combat the problem described above by modulating targeted drug-receptor effects to create new drug combinations which are safer and more effective. EP’s methodology combines an agonist, which triggers a response from the receptor, with an antagonist, which produces no response from the receptor and can block the action of the agonist, in a calculated formulation in order to optimize the drug’s efficacy while curtailing desensitization. EP has shown promising research for improving products used to treat heart failure and asthma. Additionally, EP believes that drugs used to treat Parkinson’s disease, memory loss and other diseases can be enhanced to reduce patient tolerance.

EP does not yet have a website, but the technology was transferred from Bio Balance, and one can obtain more information about their philosophy and technology on the Bio Balance website. EP’s goal is to license the technology to pharmaceutical and biotech companies so that these companies can develop safer, more effective new products and enhance (and potentially extend the patent life of) their existing product lines.

In my limited research (within the first 10 pages of some Google searches), I did not find any competitors for EP nor did I find anyone refuting the ideas and technology put forth by EP/Bio Balance. However, it may be safe to assume that pharmaceutical companies, small and large, have put significant resources toward developing similar/competing technology. On the other hand, this type of technology brings the ethics vs. profit question into light for Big Pharma. While companies have an ethical duty to put forth the safest and most effective products, they may not be able to sell as much of their product if they do. If they are able to create a product that does what it is supposed to do for as long as the patient needs it without a build up of any kind of tolerance, then the patient will never need to increase dosage (such as taking two pills instead of one) and there will be less of a need for more costly variations/extensions of the same product (e.g. extra-strength” variations). Do pharmaceutical companies really want this technology? EP is betting that they do.

EP hopes to start Phase 1 clinical trials of their technology in the near future. Ideally, the clinical trial process will prove that the technology works and provide answers to some of the following questions:

• Over long periods of time, do the combination products retain their efficacy or does desensitization eventually occur? This question may or may not be answered in clinical trials depending on the amount of time it takes to build up tolerance.
• Will the formula work the same for everyone? Different people build up tolerance at different rates. A drug’s efficacy varies from person to person. Will EP’s formula work the same for everyone or will the ratio of agonist-to-antagonist need to change from person to person?
• What new side effects will appear with the agonist/antagonist combination products? While the adverse affects for agonist alone and antagonist alone may be well known, unexpected events may occur when taken together.

EP’s methodology is certainly something to watch in the coming years. If EP can demonstrate that their technology really works and drug companies buy into it, then consumers can look forward to drug products that get the job done safely every time.