Compassionate Use

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A Compassionate Use approach is sometimes the last avenue available in treating rare conditions/diseases or a terminal illness when there is nothing else on the market to treat the condition/disease.  As you are aware, conducting a compassionate use clinical trial is a way “to treat a patient with a serious or immediate life-threatening disease or condition who has no comparable or satisfactory alternative treatment options” It is important to remember that investigational drugs have yet to be approved by the US Food and Drug Administration (FDA), they are experimental and have not been proven to be safe and effective.

FDA regulations allow access to investigational drugs for treatment purposes on a case-by-case basis for an individual patient or a group of patients. It is important to note that the “drug manufacturer and the patient’s physician must make special arrangements to obtain the drug for the patient. These arrangements must be authorized by the FDA. These safeguards are in place to avoid exposing patients to unnecessary risks”. To review the FDA regulations with regard to obtaining access to investigational drugs outside a clinical trial go to http://www.fda.gov and search “compassionate use”.

Ethics and Compassionate Use

Ethics and Compassionate Use is a catch 22 and may be considered polar opposites because when you are conducting a compassionate use clinical study with an unapproved (investigational) drug safety and efficacy have not been fully established/proven. However, Compassionate Use treatment may be the last ditch effort;  It is important to note that the treating physician has to agree that there is no other options and the patient may benefit from the experimental treatment; lastly, the company that makes the drug agrees to provide it. Many individuals are of the opinion that it is not ethical to provide unapproved drugs to anyone regardless of their medical condition. Treating with an investigational drug or device may prolong a life, may improve one’s quality of life and may provide hope to loved ones. Safety is always on the forefront of everyone’s mind especially the clinician since with the investigational drug the patient(s) may be introduced to un-necessary risk and thus, ethics and concerns are raised even though informed consent is provided.

In managing Compassionate Use Programs, I have seen the positives and negative outcomes but in the long run I do embrace the option, provided that the patient is fully informed and is of sound mind.  Recently, there was an article in the Boston Globe about getting access to Compassionate Use drugs from a parent’ perspective http://alturl.com/f39sx that is worth reading

Monitoring Clinical Trials Remotely

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I am utilizing the term “remote monitoring” to mean a remote evaluation of the clinical data carried out by sponsor personnel or a representative at a location other than the investigative site.

 The monitoring techniques that I followed and understood for several years, was that a monitoring visit was conducted at the investigative sites every 4-8 weeks depending on site enrollment and 100% source Data Verification (SDV) was conducted to insure subject protection and the overall quality of clinical study. However, as many of you are aware, this approach was resource and cost intensive. Also, this approach did not necessarily ensure the quality of the clinical trial data. It has been several years since the FDA issued a guidance regarding Risk Based Monitoring (RBM) and in my opinion many sponsors/representatives have focused on the risk and not so much on developing innovative approaches to improving the effectiveness of monitoring. For example, developing a monitoring plan that includes remote monitoring – Risk Base Monitoring and being aware of the electronic technologies available is an effective use of time and energy rather than focusing on reasons why remote monitoring – Risk Base Monitoring will not work.

 A point to consider; it has been determined that the majority of findings identified during on-site monitoring visits can be identified during a remote monitoring visit as well. Remote monitoring continues to allow sponsors to meet their regulatory obligations, while continuing to enable clinical trials to be safe but enabling them to be quicker and economically executed. I certainly understand that the small Biotech is nervous about moving away from On-site monitoring and 100% Source Data Verification due to the fact that they want to ensure that they are providing quality clinical data to the FDA. In my opinion, some small biotech company feels that the only way they can stand behind the quality of the clinical data and thus, the clinical trial is to conduct On-Site monitoring visits where they can review all aspects of the clinical trial. Perhaps, a monitoring plan that allows for both On-Site and remote monitoring – Risk Base Monitoring at different times points during the clinical trial is a more comfortable approach to take.

 The “FDA suggests that regular on-site monitoring every four to eight weeks with 100% Source Data Verification (SDV) is no longer called for in modern research, particularly due to the technological advances that make it possible to monitor data quality more efficiently. The agency proposes that the use of a centralized, risk-based approach (remote monitoring) can reduce the cost of site monitoring, with the ultimate goal of enhancing the protection of human subjects” The clinical trial staff at the investigative sites also needs to be tech savvy but not tech experts, internal site quality process needs to be updated accordingly and the investigative staff will need to be flexible, understanding the sponsor will be utilizing new techniques and processes instead of the old way of monitoring clinical trial data.

 Amazingly, some sponsors and sponsor representatives are still embracing the On-Site monitoring process and focusing on what could go wrong rather than the positives and understanding the intent of the FDA Guidance. I am hopeful that we will all take that critical step forward and embrace the change that is on our door step.

Electronic Trial Master Files

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As many of you know who are involved in clinical trials, the Trial Master Files (TMF) should consist of essential documents, which enable both the conduct of a clinical trial and the quality of the data produced to be evaluated. “The Code of Federal Regulations states in 21 CFR 312.50 that, Sponsors are responsible for ensuring that the investigation(s) are conducted in accordance with the general investigational plan and protocol(s) contained in the IND.  The European Directive 2005/28/EC states that, the trial master file shall consist of essential documents, which enable both the conduct of a clinical trial and the quality of the data produced to be evaluated.  ICH GCP, Section 8.1 defines these Essential Documents as those that individually and collectively permit evaluation of the conduct of a trial and the quality of the data produced.  These documents serve to demonstrate the compliance of the investigator, sponsor, and monitor with the standards of GCP and with all applicable regulatory requirements”.

For several decades paper documents have been the standard in setting up and maintaining essential documents related to a clinical trial. These paper documents are kept in physical file cabinet(s) that are fire and water proof. However, some companies continue to use paper even though there is an effort to reduce the cost and electronic Trial Master Files do reduce costs. The FDA created CFR 21 part 11 to support the use of electronic records, digital media and digital signatures in clinical trials. That being said, you can move from a paper base TMF to an electronic TMF and still be in compliance. Of course, I am sure you are aware of the part 11 guidance. The guidance can be found in its entirety on the FDA website. It is my hope that greater than 90% of Biotech/Pharma companies will embrace an electronic format rather than a paper format.

For your information, “in September 2013 non-profit CareLex and SureClinical Inc. initiated an eTMF standards initiative under the OASIS open standards development organization for the development of a global eTMF standard. The initiative, known as the OASIS eTMF Standard Technical Committee, has a stated objective to “define an open, internationally recognized standard that will assure information interoperability among clinical trial stakeholders in the BioPharma industry. As of July 2014, a list of members in the OASIS eTMF Standard TC includes CareLex, Forte Research, Fujitsu, HL7, Mayo Clinic, NextDocs, Oracle, Paragon Solutions, Phlexglobal, Safe-BioPharma, SterlingBio, and SureClinical”

Social Media – Subject Recruitment in Clinical Trials.

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 The number one challenge in keeping a clinical trial on track is subject enrollment. Subject enrollment is a topic that should be addressed when the clinical trial is first initiated at the investigative site however, subject enrollment goals and objectives are often thought of when goals and objectives fall quiet short of expectation. Perhaps, at the site initiation visit subject recruitment strategies should be discussed.

The Social Media Venues to be discussed;

  • Twitter
  • Intranet
  • Facebook
  • YouTube

The regulatory implication regarding the use of social media should certainly be discussed especially since it is the elephant in the room that everyone is trying to ignore. Usually, Institutional Review Boards (IRBs)/Ethics Boards will need to approve advertisement and recruitment material prior to their use; the aforementioned is considered advertisement. I have found many clinical research centers are very conservative and many times will not embrace new processes.

The following guidance http://alturl.com/8r2 is very familiar to us involved in Drug Development but as you are aware, the guidance has not been updated, given the social media platform of today. A survey conducted by the Tufts University Center for the Study of Drug Development “found that the use of social media in clinical research is minimal – so much so that most companies have yet to develop policies and practices in this area.  FDA has made it very clear that they are not going to make platform-specific guidelines, like how to use Facebook, how to use Twitter, etc. for subject recruitment especially because they feel social media is still evolving. The Tuft survey found that only one in five firms that employ social media have used it to engage with patients, leaving it to third parties like patient advocacy groups or limiting their forays to banner advertisements.” Even though the majority physicians (> 85%) under 55 years of age use some sort of social media. It has been stated that “if industry wants to use social media, they have to embrace ambiguity” and of course, in the Pharmaceutical industry ambiguity is not embraced, so what is the answer? The key elements involved when dealing in ambiguity is to use your judgment. Pharma should begin the discussion regarding the use of social media for subject recruitment in clinical trials early, take the lead in developing guidelines and policies regarding subject recruitment in clinical trials and partner with Investigative sites, as well as with CROs

Biotech/Pharmaceutical – Bubble or Bust

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In the last few years, the US is trying to bounce back from unbelievable unemployment and almost zero growth in the economy. Although, at the height of the US recession and very bad economic times, it seemed like the Biotech/Pharma industry was not as negatively impacted as other sectors. Advancing to 2015, Pharmaceutical Companies have announced $102.3 billion in biotech stocks were the market’s hottest investment.

The “S&P Biotech Select Industry Index has grown 34.31%, while the DJIA and the S&P 500 have only appreciated 2.97% and 6.7% respectively, meaning that in 2014, biotech has outperformed the market by an even larger margin than in 2013. This conveys the strength of the life science/Healthcare sector and shows that a stable framework is in place for further expansion”. However, it is important to point out that “rough estimate shows that only 30% of the 150 companies that make up the biotech index are profitable. Only 30% High-potential, no-profit biotech stocks are the most likely to come down as investors become less willing to pay up for growth”. Top Biotech Stocks to watch in 2015 are, Gilead Sciences, Inc. (NYSE/GILD), Alexion Pharmaceuticals, Inc. (NASDAQ/ALXN, Grifols, S.A. (NASDAQ/GRFS) and Biogen Idec (NASDAQ/BIIB).  “There are always challenges bringing drugs to the market. Additionally, if you look at the cost of getting a new drug to the market, depending on the methodology of how you evaluate it, it can be anywhere from $500 million to $2 billion to get a drug candidate through the incredibly arduous pre-clinical, clinical and regulatory process just to demonstrate safety efficacy and tolerability to the satisfaction of the FDA”, in the opinion of the market the above mentioned biotech companies were successful in meeting the FDA demands. “Even when a drug gets to the phase 3 development stage, the probability of failure can be as high as 50 percent (depending on the therapeutic category.). Biotech companies tend to be highly resilient, able to reinvent themselves—they tough-out these disappointments. The passion, intellect and determination of committed scientists and clinicians remain undaunted, even emboldened by the challenges of drug development”

Recently, Biotech/Pharma companies have managed staffing challenges by implementing reorganizing/restructuring which has resulted in layoffs. Companies must identify staffing vulnerabilities and design in order to reduce layoffs. “Many of the people working in biotech companies hold advanced degrees and have highly specialized technical and nontechnical expertise. They are typically strongly value human life and hold a deep commitment to creating new therapeutics, medical devices or diagnostics that improve medical treatments or meet unmet medical needs”, because of this, it can be very difficult for individuals in the biotech/Pharma industry laid off to find another job in a timely manner (~6 months).

Biotech/Pharmaceutical – Bubble or Bust

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In the last few years, the US is trying to bounce back from unpresented unemployment and almost zero growth in the economy. Although, at the height of the US recession and very bad economic times, it seemed like the Biotech/Pharma industry was not as negatively impacted as other sectors. Advancing to 2015, Pharmaceutical Companies have announced $102.3 billion in biotech stocks were the market’s hottest investment.

The “S&P Biotech Select Industry Index has grown 34.31%, while the DJIA and the S&P 500 have only appreciated 2.97% and 6.7% respectively, meaning that in 2014, biotech has outperformed the market by an even larger margin than in 2013. This conveys the strength of the life science/Healthcare sector and shows that a stable framework is in place for further expansion”. However, it is important to point out that “rough estimate shows that only 30% of the 150 companies that make up the biotech index are profitable. Only 30% High-potential, no-profit biotech stocks are the most likely to come down as investors become less willing to pay up for growth”. Top Biotech Stocks to watch in 2015 are, Gilead Sciences, Inc. (NYSE/GILD), Alexion Pharmaceuticals, Inc. (NASDAQ/ALXN, Grifols, S.A. (NASDAQ/GRFS) and Biogen Idec (NASDAQ/BIIB).  “There are always challenges bringing drugs to the market. Additionally, if you look at the cost of getting a new drug to the market, depending on the methodology of how you evaluate it, it can be anywhere from $500 million to $2 billion to get a drug candidate through the incredibly arduous pre-clinical, clinical and regulatory process just to demonstrate safety efficacy and tolerability to the satisfaction of the FDA”, in the opinion of the market the above mentioned biotech companies were successful in meeting the FDA demands. “Even when a drug gets to the phase 3 development stage, the probability of failure can be as high as 50 percent (depending on the therapeutic category.). Biotech companies tend to be highly resilient, able to reinvent themselves—they tough-out these disappointments. The passion, intellect and determination of committed scientists and clinicians remain undaunted, even emboldened by the challenges of drug development”

Recently, Biotech/Pharma companies have managed staffing challenges by implementing reorganizing/restructuring which has resulted in layoffs. Companies must identify staffing vulnerabilities and design in order to reduce layoffs. “Many of the people working in biotech companies hold advanced degrees and have highly specialized technical and nontechnical expertise. They are typically strongly value human life and hold a deep commitment to creating new therapeutics, medical devices or diagnostics that improve medical treatments or meet unmet medical needs”, because of this, it can be very difficult for individuals in the biotech/Pharma industry laid off to find another job in a timely manner (~6 months).

Vaccinations

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The need to be vaccinated against the measles virus has been in the news for weeks. It is hard to believe we are having this discussion in 2015; if I did not know better, I would think that the USA was a third world country; believe it or not the measles was declared eliminated in the United States in 2000 which means, the virus is usually brought into the USA by international travelers and we only had sporadic outbreaks; now we are dealing with a resurgence of the disease in the United States primarily because of the lack of vaccination. I am obviously in the “get vaccinated” camp. As you are probably aware, the measles outbreak has been linked to Disneyland in California in mid-December 2014 and the outbreak has now been reported in 14 States. Besides California, Arizona is the next hardest hit State.

I do understand some parents are of the opinion that vaccines cause Autism. However, to date “many studies that have looked at whether there is a relationship between vaccines and the autism spectrum disorder (ASD) and to date, the studies continue to show that vaccines are not associated with ASD”. Please review the Center for Disease Control and Prevention (CDC) Website http://alturl.com/t2fm7 . I have also heard from parents that the vaccine has peanut oil and my child is highly allergic. Please note, that vaccines do not contain either corn or peanut oils. Additionally, you can view vaccine ingredients via the CDC website http://alturl.com/bik68

There is a relatively small group of parents in a big country who have decided not to vaccinate their children however, their decision not to vaccinate their children can have a profound impact on public health. Interesting information,” Most parents who do not vaccinate do believe vaccines are necessary to protect the health of their children but also believe their children could suffer from the vaccines themselves”.

Approximately 25 states allow philosophical exemptions or religious exemption. Of course, because of health complications, some children should not be vaccinated and it is because of these children why vaccination is so important. In 2013-2014 in the entire US there were approximately 1000 medical exemptions but over 17,000 philosophical exemptions. Mississippi and West Virginia do not allow religious or philosophical exemptions, and they reported only about 50 medical exemptions.

The measles disease is extremely contagious for the following reasons:

  • “An infected person can spread it four days before developing a rash.
  • 90% of people who are not immune and are close to someone with measles will also get infected.
  • The virus is airborne.
  • It can also live on infected surfaces for up to two hours”.

As I stated previously , I am in favor of immunization coverage in the United States and I hope that many parents who are not in favor of having their children being vaccinated will change their mind.