Category Archives: Regulatory

Publishing Clinical Trial Data: The Who, What, Where, When, And Why

Gold Pill Capsules

Proposals for the full disclosure of all clinical trial data, both positive and negative, could have important impacts on the safety of new therapeutics.

By:   Joan Rachlin, JD, MPH, Executive Director of Public Responsibility in Medicine and Research

Some of the most hotly debated questions making the rounds these days include who should interpret, distribute, review, and receive data, and with good reason. From WikiLeaks to National Security Agency whistleblowers, the problems of data privacy, data security, data accuracy, and data availability are making headlines.

Over the summer I read a piece in The New York Times about Peter Doshi, PhD, a 32-year-old post-doctoral fellow at Johns Hopkins University, who has been pressing pharmaceutical companies to make their clinical trial data public. Dr. Doshi contends that financial conflicts of interest and publication bias in journals necessitate public disclosure so that consumers and patients can make fully informed decisions regarding their own care. It is well-documented, for instance, that only half of all clinical trials are published, and that negative results, which are at least as instructive as positive ones, rarely see the light of day.

Although one can hardly imagine a more David-and-Goliath-like match, Dr. Doshi and his allies have made some inroads, most notably in helping to persuade GlaxoSmithKline to commit to sharing detailed data from all global clinical trials conducted by the company over the course of the past 13 years, although nothing has yet been released.

Dr. Doshi and his colleagues’ quest for clinical trial transparency began during their work to determine whether or not Tamiflu, manufactured by Roche, was an effective treatment for flu. Their pursuit proved difficult because the bulk of the data on which claims about Tamiflu’s efficacy were based was unavailable. Only two out of ten key Tamiflu trials used to demonstrate the drug’s efficacy had been fully published, and when scientists at the Cochrane Collaboration, a well-respected network of independent researchers working with Dr. Doshi, tried to track down the other eight, they hit repeated road blocks. As a result of the missing data, the Cochrane Collaboration determined that they could not endorse Tamiful’s effectiveness, a move which prompted Roche to open its file cabinets and join GlaxoSmithKline in its commitment to share detailed data with outside researchers.

There are other cases fueling the call to require data publication as well. In June, for example, two independent reports indicated that Medtronic’s spinal surgery product, Infuse, carried with it serious risks, including cancer and male infertility, and that there was no demonstrated improvement over already-existing products for the same purpose. The reports, prepared under the auspices of Yale University with funding from Medtronic, examined 17 studies. The news reports surrounding these revelations are rife with allegations that negative data was suppressed, that conflicts of interest abounded, and that Medtronics promoted off-label use.

The efforts of Dr. Doshi and the Medtronic example, especially when combined with the recent European Medicines Agency’s proposal requiring wider access to patient-level trial data, have contributed to growing public demand for information that was formerly within the sole province of researchers, clinicians, and journal editors. The Pharmaceutical Research and Manufacturers of America (PhRMA), as well as most drug companies—excluding GlaxoSmithKline and Roche—have opposed this push. Some argue that American consumers already have access to raw data via the federal clearinghouse, but others contend that this is inadequate as there are extensive limitations placed on what kinds of information can be released through that medium.

These issues around data transparency and review, among so many others that are rapidly changing the research landscape, could have long-term implications for research and development. One of the concerns being voiced by members of the pharmaceutical industry is how such policy shifts might hamper innovation. John J. Castellani, president and CEO of PhRMA, has been a vocal opponent of the proposed regulatory changes from the EMA and other reforms that he claims are too broad in scope. “Public policies that value intellectual property, a strong regulatory system, and free market access for patients are critical to a robust innovation ecosystem and new progress in the fight against disease,” he argues. The threat at the heart of Castellani’s comment, of course, is that as clinical trial data becomes widely available, so do information that has long been commercially protected.

The development of new drugs is a costly and lengthy endeavor. The high costs associated with developing and bringing new drugs to market have long been tempered by the potential profits that can be achieved when drugs find mass success. In their opposition to the data transparency movement PhRMA raises the question, if data from the drug development process becomes publicly accessible will the incentive structure that has helped fuel the development of new drugs be undermined?

On the other hand, perhaps the ethical imperative of data transparency demands a paradigm shift. Ben Goldacre a noted proponent of clinical data transparency asserts “that the problem of missing trials is one of the greatest ethical and practical problems facing medicine today.” Sharing of clinical trial data allows for results to be double checked and critically appraised, and means less duplication of effort, greater collaboration, reductions in drug development times, greater public trust in the pharmaceutical industry, and ultimately better protections for healthcare consumers.

From the EMA’s proposal to the moves being made by companies such as GlaxoSmithKline and Roche, the tide has shifted toward data transparency. The question that faces research professionals now is exactly what should the sharing of clinical trial data look like. Proposals have emerged on both side of the debate—from PhRMA to the AllTrials campaign led by Ben Goldacre— which could shape the future of the clinical research enterprise. For those invested in the conduct of clinical trials, now is a pivotal time to engage in the conversation surrounding data transparency. Do you think public access to clinical trial data should be provided? And if so, how?

Picture Credit:  Bill David Brooks via photopin cc

Orphan Drugs: Are They Worth It?

Stormy sky over ocean

The Orphan Drug Act continues to bring hope to patients with rare diseases while providing the guidance and incentives that companies need to develop desperately needed therapeutics.

By:  Kelsey McCormick, MS

Nearly a year ago, I was scrolling through my news feed on Facebook (yes, one of my guilty pleasures!) and came across a very disturbing picture of a newborn with horrible blisters and open sores all over his body.  With immediate heart ache, I had to know his story.  I found out he was suffering from Epidermolysis Bullosa (EB), a rare genetic disorder that causes the skin to be so fragile that the slightest touch or friction can cause severe and painful blistering—internally and externally.  My eyes filled with tears seeing this poor baby and his family.  I have followed him on Facebook for nearly a year.  He struggles with severe pain every day, constant bandage changes, infections, lengthy hospitalizations, etc.  Why had I never heard of this?  What is being done for this poor, helpless baby?

Thanks to Facebook, I am now AWARE.  And awareness is what will ultimately spread the word and help those suffering from these horrible unmet medical need.

The orphan disease challenge
EB is classified as an Orphan Disease because it affects less than 200,000 people in the U.S.  It’s such a horrible disease and therefore low prevalence is a good thing!  But . . . the bad thing is pharmaceutical companies are typically less motivated to develop treatments for diseases that only affect a small number of people.  The generated sales are usually minimal compared to those with a cancer that affects a larger population (e.g. breast cancer or prostate cancer).

But what about this poor baby suffering on a daily basis?   Not to mention the suffering of his parents and siblings (and the family wallet!).  How can we help him?

 A winning solution for patients and pharmaceutical companies
Thankfully, Congress recognized the unmet medical needs and the lack of treatments/therapies for many rare diseases, which led to the passage of the Orphan Drug Act (ODA) in 1983.  The ODA provides incentives for the development of Orphan drugs (See associated Regulations here:  Code of Federal Regulations, Title 21 Food and Drugs, Part 316 Orphan Drugs).  Shortly thereafter, the Office of Orphan Product Development (OOPD) within the FDA was formed to help guide the Sponsor Companies through the complex regulatory pathway of an Orphan drug from discovery to market.  As one would hope, the passing of the ODA and its incentives has led to a major increase in the market approval of new therapies for Orphan diseases.

There is hope, much hope, for my little, precious Facebook friend!

Special opportunities for companies developing orphan drugs
Naturally, one would ask, “What are the incentives of developing a treatment or therapy for an Orphan Disease?”  To list a few:

  • The Prescription Drug User Fee (PDUFA) is waived. And they aren’t cheap! See below for fee rates for FY 2013

Fee Table

  • There is a 50% tax credit to help defray clinical study costs
  • Eligibility to apply for the FDA Orphan grants program
  • 7 years marketing exclusivity

Those are some good incentives!

Now what?  How do we do this?  What are the next steps?

In order to obtain the above incentives, the Sponsor Company must apply for Orphan Drug Designation with the FDA and if “approved,” the FDA will grant the Sponsor Orphan Drug Designation in writing.  Specific instructions can be found here:  How to apply for Orphan Drug Designation

Is it worth it?
It sure is.  Take a few minutes to Google Epidermolysis Bullosa and perhaps a story or two will catch your attention just like my little EB baby Facebook friend caught mine.  Within minutes, I would bet my glass of wine (and anyone that knows me, that’s huge!!) that you will feel the “real” motivation towards finding treatments and cures for the many unmet medical needs.  The incentives from the ODA are just icing on the cake. 

Key Tips for Success with Orphan Drugs

  • Motivation for your company’s goals is critical . . . the path to market for an Orphan Drug has many gray areas . . . there’s no easy answer, so one must have true commitment and passion for the suffering patients whose finger is in the pill vial or arm is at the tip of the syringe.
  • Attempt to obtain Fast Track Designation with this, the FDA will be more proactive and help facilitate the development and expedite the review of drugs intended for an unmet medical need.  All in hopes to get the drug to the patient faster!
  • Defining meaningful biomarkers early can help in selecting a quantifiable clinical endpoint and accelerate completion of this process.
  • Early and consistent communication with the FDA is critical before and during the development of your Orphan drug (or any drug for that matter!).

Picture Credit:  zoomion via photopin cc

Never Giving Up After Failure Will Lead to Success

By: Kelsey McCormick, M.S.

Sky with sun and clouds

The passion of your team with the guidance of a regulatory expert will be critical factors in getting the approvals you need for commercial success.

You have to work through the “wrong” ones to get to the “right” one. What does that make you think of? It makes me think of 2 things: 1) Relationships, and 2) Drug Development. I know, you’re thinking, “huh?”

Think about it though . . . dating . . . how many people did you date before you found your “Mr.” or “Mrs. Right?” (Those who are still looking don’t give up!) Think of all the time, emotions and money spent on the “wrong” ones! In my case . . . there was a lot of “sifting” until I found my loving hubby (Brownie points if my husband actually reads this! Better yet, if he doesn’t mention this, he’s sleeping in the shed tonight because it means he didn’t read my newsletter!). It was from those “Mr. Wrongs” that I learned what I ultimately wanted (or didn’t want!) in a life partner! I am now happily married (10 years already!) with two wonderful kids (cue cheesy love song).

The regulatory challenge of drug development
Drug development . . . as you all probably know (and experience!), there is much failure in this amazing, but challenging industry we live in! It can be frustrating and draining to spend so much time, money and even emotion on a product, to then have it fail in Clinical Trials and never make it to market (cue depressing break-up song).

“In general, it costs an average of $800 million and takes 12 to 15 years before a drug makes it from the lab bench to your medicine cabinet!”(1)

The regulatory roadmap
It’s tough to summarize activities over 11-14 years, but in short (as most of you know), the process goes like this:

Drug discovery begins with an idea for a new disease target, often licensed from a university laboratory.

–Industry researchers start sifting through hundreds (sometimes thousands!) of compounds, looking for one that will hit the biological target.

–The lead candidate is tested in animals to look for toxic side effects and potential efficacy.

–IND Phase: clinical trials in humans. These trials eat up much of the development costs.

  • Phase 1: small number (about 20-80) of healthy volunteers to assess safety
  • Phase 2: medium number (about 100-300) of patients (affected by the disease the drug is indicated for) to assess efficacy, safety and pinpointing acceptable dose range
  • Phase 3: large number (about 1000-3000) of patients to assess efficacy, safety and identify side effects.

And even more depressing . . . only about 1 in every 5,000 drugs in development actually make it to market.

What you need to successfully navigate the regulatory roadmap
Talk about a high failure rate (kinda like youngins dating)! YUK! There’s a ton of detail that goes into the above lengthy process. It takes a lot of brains (like yours), a lot of hard work (like mine), and a lot of hope (optimists) to get to market.

In trying to find the bright side of each of these depressing realities, which in turn will help motivate us: as you see, the cost to develop a drug is ridiculously high . . . this helps me feel a little better when I go to buy an OTC or prescription drug and my wallet is quickly emptied! And with the high failure rate, I’m very comforted in knowing how detail-oriented, diligent and CAREFUL drug companies and the FDA are when developing these products and reviewing the data. Makes me feel a little safer knowing the process isn’t rushed just to get a drug on the market.

So how do we continue on with our daily jobs knowing the painfully low success rate in our industry? In my mind, it’s all about perspective, persistence and positive thinking.

Quick Tips:

  • As in dating, we have to weed through the bad ones to get to the good one! DON’T RUSH IT. There’s no turning back (well, not easily and pain-free anyway)!
  • Each failed drug or failed relationship is NOT a waste of time or money. TONS of useful information is gained from these processes. Stay positive no matter the results, and be proud of the work accomplished.
  • Take advantage of all the years of knowledge that’s out there (literature, colleagues), and consider similar products that have failed and/or been approved. You’ll have a head-start!
  • Know your competition . . . risk of failure is that much higher when someone else is developing a similar product with the same disease indication.
  • Have passion for the product you are developing . . . that helps maintain the positive attitude and “I won’t give up” mentality!

I won’t give up, every day that passes; every lesson learned . . . we are that much closer to ‘the one’.”


  1. Cost and time line estimates based on over 15 years of industry experience of McCormick LifeScience Consultants, LLC.

Picture Credit:  © Mihalec | Dreamstime Stock Photos & Stock Free Images