ALS FUNDING TWEET & SOCIAL MEDIA STORM TO CELEBRITIES (AUGUST 28-31)

ALL #PALS and #CALS, the most important thing you can do this weekend is use your FB, Twitter and other social media accounts to raise money for ALS research and treatment.  We only have a few days left in August to make some noise.  Reach out to your favorite celebrities and spread the word to all #PALS, #CALS, and advocates to do the same!       

ALSTDI says donations for #IceBucketChallenge are down 98% from last year.  We need to keep private donations at the same level or higher than last year in order to continue to make headway towards a cure for #ALS.  There are a few more days left in August and the video craze may unfortunately have lost celebrity interest.  PALSFirst would like to post the names of those celebrities who donated money, an incentive for them to show us how wonderful they are!  

This Weekend (AUGUST 28-31), please use your FB and Twitter Accounts to challenge your favorite celebrities (actors, musicians, athletes, etc.) to donate at least $5 towards critical research and treatment.  There are of course multiple organizations in need of funds so feel free to tweet in favor of the organization of your choice.  #PALSFirst supports #ALSTDI because all donations goes towards research including their #PrecisionMedicine program and #ALSETF because they are working with industry to get #ExpandedAccess Programs, which will allow #PALS not qualifying for #clinicaltrials to get access to experimental drugs and treatments.

Here are two suggested tweets:

 #IceBucketChallenge $ LOW, Plz [@celebrityname] donate $5 to @ALSTDI @ALSETF for critical #ALS research & treatment for dying #PALS, RT 

[@celebrityname] if donated $5 or more to @ALSTDI @ALSETF for #ALS, plz RT so @PALSFirst can congratulate your caring & awesomeness!    

White House Precision Medicine Initiative: Are the Risks Worth the Gain?

“Doctors have always recognized that every patient is unique, and doctors have always tried to tailor their treatments as best they can to individuals.  You can match a blood transfusion to a blood type-that was an important discovery.  What if matching a cancer cure to our genetic code was just as easy, just as standard?  What if figuring out the right dose of medicine was as simple as taking our temperature?” -President Obama, January 30, 2015

In January 2015 during the State of the Union Address, President Obama announced his plans to launch The White House Precision Medicine Initiative (PMI), a revolutionary approach to the way we collect, conduct, and share disease research. 

The overarching goal of the White House PMI is to create a global warehouse of electronic medical and science data from diverse data sources including medical records, genomics, lifestyle and environment, and personal device/sensor data.  Currently these types of data are collected inconsistently, using different methods, and stored across organizations and agencies such as medical clinics, hospitals, healthcare and insurance systems, state and federal health departments and other state and federal agencies, clinical trial locations, and private pharmaceutical and biotechnology companies. 

Those in research are often frustrated by this reality because it takes a lot of time and money to request data from these various sources.  When data is provided it is aggregated and does not allow the researcher to link individuals across data sources, which would allow scientists to answer several important research questions.  For example, if set up correctly such a data warehouse would give scientists the ability to identify specific chemical or other environmental exposures, lifestyle habits, and genetics and molecular pathways associated with disease.  Knowing this will better enable public health to provide recommendations for maintaining good health and preventing disease.  It would allow regulatory agencies the ability to more accurately create safe exposure limits on chemicals in our environment.  And it would allow clinical researchers to develop tailored treatments for both common and rare diseases, and treatments that would be effective on an individual’s specific type of disease based on their genetics with minimal side effects. 

In March 2015, the White House convened an interagency working group charged with developing a set of privacy principles for PMI.  On July 8, the White House held a live-streaming conference to discuss the Precision Medicine Initiative and publicize the following:

·        White House PMI Website

·        Patients who have benefited from precision medicine

·        Individuals and Organizations who are supporting the PMI, known as White House Champions of Change (#whchamps)

·        The Interagency Working Group Proposed Privacy and Trust Principles for public comment (due by August 7, 2015).  

The President’s PMI plan is to focus on cancer first then build in other diseases including rare diseases such as ALS/MND.  The PMI will enlist 100,000 patients to volunteer in a pilot study that will help the Interagency Working Group to refine their procedures and policies required to implement the larger project.  In order for this to be a success, the White House needs patient buy-in that they are trying to garner through these Champions of Change supports, opportunity for public comment on proposals, and outreach through social media.    

PALS Campaign reviewed the Precision Medicine Initiative: Proposed Privacy and Trust Principles document.  We feel that the PMI is a very ambitious project with laudable goals, however we are gravely concerned about the inherent data privacy issues with attempting such a large-scale, and globally accessible project and have a number of questions.

Who will be the primary data holder(s) and what will this data system look like? How will the White House protect against cyber attacks and network hacking?  And how can we be assured that personal health information will be used strictly for the research purposes intended under the PMI? 

Having one entity responsible for warehousing the data, for example the National Institutes of Health (NIH) or Centers for Disease Control (CDC), would hopefully insure better data accuracy and consistency, however this would pose a greater data security risk.  Look at the recent U.S. federal data breach of 22.1 million federal employees and their family members where the Chinese government is said to have stolen American home addresses, social security numbers, mental and criminal background checks and fingerprints.  The size and nature of such a cyber attack does not really increase a sense of safety when it comes to signing over information on your full DNA profile and other personal health information.  And what about people who work for the agencies themselves?  What restricted access protocols will be in place to insure that data breaches don’t occur within the system? 

We believe the best architecture for a PMI data warehouse would be to operate it similarly to how other active health reporting/surveillance systems work.  Federal agencies will work with clinical researchers, epidemiologists, patients, advocacy organizations, etc… to develop a set core of measures and datasets that will be compiled.  These protocols will be provided to states with training.  State agencies work with the various data holders, e.g. medical clinics, hospitals, healthcare systems, etc… to link data sources to individuals.  The database is then cleaned so that errors are corrected and each individual is given a unique identifier known only to that agency.  States send their database updates to the responsible federal agency (e.g. CDC, NIH) who will compile state data into a national database.  In this architecture, individual data can be linked to the various data sources, but will be de-identified at the national level. No names, birthdates, or addresses will be associated with the dataset that researchers analyze, however it can be linked back at the state level using the states known unique identifier for reporting results back to the individual.  This architecture would not 100-percent guarantee that PMI at the state level would not be breached, but would reduce the chance of a major and severe data breach at the federal level. 

What will be the Institutional Review Board (IRB) process and who will sit on the committee?  How will the White House insure informed consent is upheld?

Fundamental Assumptions About the PMI Cohort (Number 3) of the PMI document states that the intended researchers will include academic, non-profit, and for-profit entities.  It also says the scope of research will be broad-based, not only for answering specific questions but also for hypothesis generation.  Patients and study participants are a lot more cautious about signing over their personal information for research given past research abuses.  Two research frameworks that we recommend the White House use include: Community-Based Participatory Research (Israel et al, 2005) and Reality-Based Research (Poupart et al, 2009).  These frameworks include study participants throughout the process, from project design to implementation and information dissemination.  What would this look like?  Patients, their caregivers, and advocates would be included on all planning and decision committees, including the IRB.  One issue previously raised was whether or not a personal record could be contained within the database once that person has passed away and could no longer provide consent for release of their records.  We feel that every effort should be made to get informed consent for records pertaining to genome information, however in the case of death or lost to follow-up an IRB consisting of people with the disease would be appropriate representation. All information provided to patients and their family members including informed consent forms and research results should be written in plain language, health literacy, and numeracy best practices.  In keeping with an authentic partnership under CBPR and RBR frameworks, information must be in a format that will be understandable.  Common medical and scientific jargon, including presentation of data in graphs and tables is confusing for most people.  The PMI should consult with health literacy experts to insure that forms and reports are understandable.           

How will this be paid for?

Lastly, how will this system be paid for?  The large nature of the project, multiple individuals that would need to be involved, database and security development will not come cheap.  If people must volunteer to become part of this database then will the data collected be truly representative at a population level? 

White House Precision Medicine Initiative: Are the Risks Worth the Gain?  That is up to you.  Public comment on the Precision Medicine Initiative: Proposed Privacy and Trust Principles is due August 7, 2015 using an online form available at the White House PMI Website.  PALSFirst Campaign encourages all PALS and CALS to read this document and provide feedback. 

 

References

Collins and Varmus.  A New Initiative on Precision Medicine.  The New England Journal of Medicine, 372 (9), February 2015.

Nakashmia, Ellen (2015, July 9).  Hacks of OPM databases compromised 22.1 million people, federal authorities say.  The Washington Post.

Poupart, Baker, and Red Horse (2009).  Research with American Indian communities: The value of authentic partnerships.  Children and Youth Services, 31(11): 1180-1186.

Israel, Eng, Schultz et al (2005).  Methods in Community-Based Participatory Research for Health, 1^st Edition.  Jossey-Bass.

The Precision Medicine Initiative.  The White House, 2015.

Precision Medicine Initiative: Proposed Privacy and Trust Principles.  The White House, July 8, 2015.

#WhiteHouse #PrecisionMedicine #whchamps #endals #nowhiteflags #ICantWait #ALSA  

Should companies be allowed to deny patients access to experimental treatments for life-threatening diseases?

Last year Arthur Caplan and Kenneth Moch published a very thought provoking article in the Health Affairs Blog, “Rescue Me: The Challenge of Compassionate Use in the Social Media Era.”  In the article they touch on the ethics and policies of denying access to potentially life-saving treatments. 

Caplan and Moch (2014) state, “The question of whether there is a duty to pay for the use of unproven and experimental therapies to attempt to rescue individuals in dire medical straits, even those with poor odds of success, is one that health policy makers have not acknowledged as part of ongoing national health care debates in the United States and other nations…The duty to seek to rescue those in very dire straits is a powerful norm in American society and in major religious traditions around the world.  Whether it is coal miners trapped in a mine, mountaineers stranded on a peak or a child fallen in a long abandoned well, it is very clear that, despite difficultly and cost, society wants strenuous rescue efforts to be made.  Health policy discussions often fail to reflect this deep moral concern as shown in the absence of attention to the issue of ‘rescue’ and in the lack of funding in public and private insurance for attempting to do so.”    

It would seem then that unless there is in-your-face coverage of the injuries and death caused by denying patients access to potentially life-threatening disease, there will be no movement towards Expanded Access or Accelerated Access Programs for ALS or other rare diseases. 

Caplan and Moch (2014) discuss the case of 7-year old Josh Hardy who in March 2013 was denied access to the experimental drug Brincidofovir (Chimerix, Inc.).  Chimerix, the North Carolina based pharmaceutical company had previously made brincidofovir available to over 430 critically ill patients under an Expanded Access Program initiated by several individual doctor-sponsored emergency INDs in 2009, and later funded for 215 more patients through funding from the Health and Human Services Biomedical Advanced Research and Development Authority (BARDA).  It was only after a social media cry for help (#SaveJosh) followed by a smear campaign against Chimerix (#SaveJosh), which lead to televised media coverage and letters and phone calls to politicians that Hardy received the necessary treatment.  The irony of the situation is that after Chimerix released the drug to Hardy, the company was applauded online and stocks rose by fifty-percent. 

So I ask myself, why are companies developing ALS and rare disease treatments denied expanded access left and right?  Why are there only a few companies that have clear, transparent policies on Expanded Access, procedures, and contacts listed on their webpage?  Why are people who do participate in these clinical trials taken off the treatment to observe for follow-up even when their clinical measures have improved?  Why do we not yet have FDA Guidelines specific for conducting clinical trials research and expanded access programs with ALS and other rare diseases that include input from those actually afflicted? 

Speaking to advocates in cancer, HIV/AIDS, and tuberculosis, diseases where you can actually find Expanded Access Programs available, you will hear that they have faced these same issues.  It is history repeating itself.  You would think that people suffering rare, fatal diseases today would not have to suffer through the same hurdles.  What we should be doing as PALS, CALS, and advocates is work with the U.S. FDA, HHS, NIH, politicians, public and private insurance companies and pharmaceutical/biotechnology companies to overhaul the current system. 

The FDA permits pharmaceutical/biotechnology companies to conduct clinical trials in the United States. Public dollars from NIH, DOD, etc…fund their research and FDA has provided them with additional funding and expedited status for those investigating rare diseases.  In the end the companies negotiate treatment costs and extend patents to the maximum to maintain their high rates.  How are people with the disease benefiting?  How are those who participate in clinical trials benefiting when the treatment is taken away after the trial has ended?

The solution is the political will to rescue people with potentially life-saving treatments like they do for those caught in an avalanche, or buried underground.  We could require companies who conduct trials in the United States to have clear policies on Expanded Access, procedures, and contacts posted on their websites.  We could also require companies to provide a minimum quota of expanded access patients for each clinical trial they conduct.  And also require that if a treatment that is shown to be safe and improve clinical measures to a patient enrolled in a clinical trial, that they be allowed to continue that treatment once follow-up measures have been made.  It would also behoove many to create clear FDA Guidelines for clinical trials research and expanded access programs for ALS and other rare diseases in collaboration with researchers, treating doctors, companies, patients and caregivers.  When all else fails, make some noise.  Social media and televised stories can be powerful tools.        

 

    

PALSFirst Campaign Leader Dies Friday from ALS

Cheryl Anne Beede-Sweeney, courageous wife, daughter, sister, and mother of three passed away Friday, July 3, 2015 in Duluth, Minnesota after a long battle with Amyotrophic Lateral Sclerosis (ALS)/Motor Neuron Disease (MND).  

ALS, also known as Lou Gehrig's Disease is a fatal disease that rips away your ability to move, eat, speak, and breathe. Every 90 minutes someone is diagnosed with ALS and another dies.  There is no cure for ALS.  Only one drug on the market exists that prolongs life on average only three months.  Like many people with ALS, Cheryl did not qualify to participate in clinical trials due to current lengthy diagnostic criteria and strict inclusion/exclusion criteria.  Years were spent trying to access BrainStorm Cell Inc.'s NurOwn stem cell treatment via the U.S. FDA Expanded Access Program, but BrainStorm Cell Inc. denied her access to this potentially life saving treatment, thus was the birth of the PALSFirst Campaign.   

Cheryl truly was the heart and soul of the PALSFirst Campaign.  She was a natural leader, advocate, and faith-based healer.  Her smile, continuous love for others, and hope that there would be a cure someday for ALS filled others with joy.   More than anything, Cheryl wished for others suffering from ALS to have the opportunity to try new treatments through clinical trial redesign, U.S. FDA Accelerated Access and Expanded Access Programs, and policy reform.  Cheryl's presence will be greatly missed, but her legacy will live on with the PALSFirst Campaign and all those who continue to fight for access to treatments.  

Cheryl Beede Sweeney's Obituary

Empathy in Science, Medicine, and All Policies

“The moral test of a nation is how it treats those who are at the dawn of life, the children; those who are in the twilight of life, the aged; and those who are in the shadow of life, the sick, the needy, and the handicapped.”  -Hubert H. Humphrey (1976) 

Today marks the end of ALS Awareness Month, but the fight lives on for those suffering with ALS, their caregivers, close family and friends, and advocates.  On this last day of May, PALS Campaign reflects on the future of ALS research, treatments, and the community stronghold and calls for Empathy in Science, Medicine, and All Policies.    

It is humbling to see the awareness and interest in private funding for ALS grow, peaked by the efforts of the ALS Ice Bucket Challenge, numerous films and personal accounts in the social media, the Steve Gleason Act, and rallying at the Capitol over GM604.  It is with great sadness that we also realize we are likely decades away from real change.

 

HIV/AIDS and Cancer-two diseases that rose in status from diseases no one wanted to acknowledge or were too overwhelmed or scared to deal with to widespread public awareness and finally major public and private financial investment and policy change that led to the advancement of and access to treatments.  What turned the needle in favor of critical change was the marriage of radical advocacy and science. 

After several years dancing the two-step with politicians, change advocates in HIV/AIDS and Cancer realized they needed to get more radical in order to gain the media attention needed to drive political pressure and shame companies into providing experimental treatments to those suffering and dying of their diseases.  These advocates became so well organized that they knew the date, time, and location of every investment meeting for experimental pharmaceuticals, every NIH, FDA and policymaker meetings and events and every location of the biotechnology and pharmaceutical company headquarters.  Why?  Because these are the ideal locations and times to hold rallies and protest companies that deny access to treatments.  These two movements held funeral processions at company headquarters, honoring those who had asked for treatments, were denied, and subsequently died.  The larger the rally or protest, the more media attention they received.       

           

This alone was not enough to fight the war.  They needed true scholars, people who empathized with those suffering, were well read, well educated and had the necessary skills to guide the movement in the right direction.  These individuals didn’t read a few journal articles or a few web pages on the Internet and assumed they knew everything.  They looked at the issue from all angles-science, medicine, policy, advocacy and sought out content experts, those in government and policy to understand the processes behind FDA rules and regulations, scientific limitations, etc…  They asked the right questions, identified hurdles and sought big picture solutions.  They didn’t focus on one drug or blamed all their woes on one government agency.  They changed how we fundamentally look at drug development, clinical trial design, and created the FDA Accelerated Access and Expanded Access programs.

Interviews with government agency heads and policymakers said the radical protests and rallies grabbed their attention, but it was the scholars that came to them with specific solutions and knew the language of science which allowed them to make real changes that made all the difference in the world.   

Competing interests, financial drain, and low political will prevents us from moving the needle from ALS awareness to fundamental changes: major public-private financial investment in research, developing new clinical guidelines and clinical trial designs for ALS, creation of a mandatory national ALS registry, creation of a health literate, consumer friendly clinical trial search engine, encouraging Accelerated Access of experimental drugs deemed reasonably safe and effective in Phase 2 trials and Expanded Access of experimental drugs and treatments that do not qualify for Accelerated Access.  These goals are within reach if the ALS Community marries radical rallies and protests with sound science.     

PALS Campaign also calls to action Empathy in Science, Medicine, and All Policies.  There are three ways in which we engage with a disease: sympathizing, empathizing, and understanding.  Sympathizing, is feeling compassionate towards someone’s suffering.  Empathizing is getting towards the core of your feelings, trying to picture yourself in that person’s shoes.  And understanding is when someone actually has the disease.  Those with the power of decision making, the doctors and scientists responsible for researching the disease and treating patients, the businesses that hold future treatments, and policymakers that make decisions on the processes and incentives in place may show sympathy towards those with ALS.  Unless they themselves have ALS, they can never truly understand what it is like.  But the call to action is this-Let Empathy drive your decisions in science, medicine and policy.  Imagine yourselves in the shoes of someone with ALS.  If you lost your ability to walk, eat, speak and move, how would you like to be treated in clinic?  What would your priorities be in scientific development?  Wouldn’t you want policymakers, industry, government, advocates to work together to provide more options for treatments?      

The Case for a Mandatory ALS Registry

There are a lot of scientific questions that we do not have the answers to yet; answers that would allow scientists and healthcare professionals to make prevention recommendations and tailor treatments.  Why do some people get symptom onset in their 30s and others in their 50s and 60s?  Why are some people with ALS such as Stephen Hawking able to live with the disease for over 20 years when most will live only 2 to 5 years after diagnosis?  Why do some people get bulbar onset ALS, which holds a poorer prognosis, and others get limb onset ALS?  Is ALS purely genetic or could there possibly be environmental triggers such as insufficient Vitamin D intake or inability to properly metabolize Vitamin D, psychological stress, viruses and bacteria, or chemicals such as hormone disruptors?  Experts believe there are likely multiple pathways to developing ALS.

Incomplete Information in Existing ALS Registry

The only way to really answer these questions is through lab-based research, observational clinical studies and epidemiological investigations.  Money from the Ice Bucket Challenge is being poured into lab-based research, but will take several months to years to see the results.  Ongoing genetic studies based on blood, spinal fluid, and tissues are identifying and investigating the role of familial linked and other genes.  However, there is no mandatory ALS registry like there is for cancer and infectious diseases in the United States, with the exception of the State of Massachusetts.   

In 2008, Congress enacted the ALS Registry Act (PL 110-373) which charged the Centers for Disease Control and Prevention (CDC) with developing and managing the registry.  It consists of existing administrative data maintained by Medicare, Medicaid, the Veterans Health Administration and the Veterans Benefits Administration, coupled with self-reported data collected via a secure, web portal that was launched on October 19, 2010, to identify additional people who would not be captured by the administrative data.  People registering on the web portal are asked screening questions to verify their ALS diagnosis.  They are also asked information on possible risk factors such as age, race, education, income, work and military history, physical activity, alcohol and tobacco use, and family history of neurodegenerative diseases.  In addition, the Agency for Toxic Substances and Disease Registry, a branch of CDC, funds state and metropolitan registries to obtain more reliable and timely data, including demographic information such as age, sex and race and compares this data with the national registry to determine if certain groups are likely underrepresented in the U.S. statistics.  Areas that have received funding include Florida, New Jersey, and Texas State, and the metropolitan areas of Atlanta, Chicago, Baltimore, Detroit, Las Vegas, Los Angeles, Philadelphia and San Francisco. 

The current ALS Registry is a fairly rigorous registry, but certainly does not capture everyone with possible, probable, or diagnosed ALS because it is not a Census.  That is, with the exception of the State of Massachusetts (Section 26 of Chapter 140 of the Massachusetts Acts of 2003), ALS is not a mandatory notifiable disease.  Secondly, the registry cannot estimate ALS incidence (all new cases of ALS) due to the fact that 68% of the cases in the large administrative data do not have a date of diagnosis.  Third, the online ALS Registry is self-report data, which means anyone could register him or herself as having ALS.  A list of screener questions are used to try to weed out those with suspected or perceived ALS from those who actually have ALS.  However there is no good method for accurately verifying someone in this dataset has actually received a doctor’s diagnosis.    

Diseases that are designated as law binding notifiable diseases such as many infectious diseases require doctors and other healthcare providers and labs to report to the authoritative state agency any case that meets the definition for that disease ensuring almost complete capture of everyone diagnosed with ALS.  This would benefit the ALS Community because it would allow public health agencies to more accurately assess incidence (all new cases of ALS) and prevalence (overall the number of people with ALS at any given point in time).  The current registry likely underestimates the number of people with ALS, which means under times of financial strain they may not receive full priority for research dollars and resources.  It also means that agencies will not be able to detect ALS clusters and possible causal links or priority areas to focus limited resources.        
 
If you want ALS to be a national priority, tell your legislators that you want ALS to be a nationally notifiable disease. 

Reference

Mehta et al (2014).  Prevalence of Amyotrophic Lateral Sclerosis-United States, 2010-2011.  CDC MMWR Surveillance Summary, 63(SS07): 1-14.  http://www.cdc.gov/mmwr/preview/mmwrhtml/ss6307a1.htm

Rethinking Clinical Trial Designs for ALS to Increase Access and Shorten Duration

Clinical trials are a great way for people with no treatments options to try experimental drugs, therapies, and devices.  They help researchers weed out promising treatments from those who prove not to be safe or effective.  The classical clinical trial design starts by randomly selecting out two groups of participants for the study, one called the treatment or intervention arm and one called the placebo or control group.  Because there are so many factors that are difficult to control for in a statistical analysis such as normal rate of decline among each participant, types of ALS (familial versus sporadic and bulbar versus limb-onset), and unknown factors that cannot be calculated, placebo or control groups are put in place so that researchers can determine actual effects of the drug, treatment, or device.  In other words, to measure a drug’s effect you need a comparison group.  Otherwise you’ll never know if the drug is having the effect on ALS or something else in the person’s body or environment.

There are typically three phases to clinical trials. Phase 1 studies are done to determine whether or not a drug is safe and to determine a safe dose for further testing.  Phase 2 studies determine biologic activity, is there a positive effect on disease measures.  Phase 3 studies determine efficacy.  This process is expensive and arduous.  To start a clinical trial, the company must first file a Research IND with the U.S. FDA, which includes a written study protocol and previous animal or cell based research showing there will not be unreasonable harm to participants.  Clinical sites must be recruited, databases created and drug supplies distributed.  At best it takes a year to mount a trial.  Add on another year when considering the time it takes to apply and receive publically funded grants.  Clinical trial barriers therefore can be summarized by time, funding, capacity, and design.   

A major point of discussion relevant today is clinical trial designs and goals.  Researchers and industry running the clinical trials must consider feasibility of conducting the trial.  That is what are their staff, facility, and manufacturing capabilities and cost of conducting the trial.  Whereas, clinical trial goals for someone with ALS include early (faster) drug development and more opportunities to try experimental drugs and treatments.  The solution to these competing goals would appear to lie within changing the standard clinical trial design to either include more participants and/or speed up the process.

There is certainly precedence for this in the published literature.  Dr. David Byar, a statistician, in 1990 offered clinical design solutions for HIV/AIDS research, which revolutionized how we approach clinical trials research.  Gehen (1986),  Schoenfeld (2005), Schoenfeld and Cudkowicz (2008) also analyzes different designs in cancer and ALS.  Here are a few options.

• Futility design: This design is intended to speed drug development.  If shown to possibly work, then it proceeds to further studies.  In this design the null and alternative hypotheses are reversed such that the objective of the study is to prove that a drug DOES NOT work (versus typical clinical study designs where drugs have to be proven to work).  This design has good sensitivity but poor specificity.  This means that it does well at finding drugs that are effective but does not do well at finding drugs that are ineffective.  According to Schoenfeld and Cudkowicz (2008) this design could be run as a phase 3 trial with a placebo or control group and increased numbers of participants or could be run without a placebo or control group but reduced numbers of participants.  
• Lead-in design: In this design participants are followed for a 3-month period to measure average rate of decline, then treated for 6-months with a follow-up period.  This design could eliminate the need for a placebo or control group because each participant becomes his or her own control for the lead-in time.  Or a historical control could be used if assumed that there are no differences in average rates of decline by time.  Lead-in designs can also allow a researcher to decrease the number of participants needed in the study.  By decreasing the number of participants, however the final analysis must assume that someone’s average rate of decline in the 3-month period before treatment will be the same throughout the study (non-robust analysis).  In the robust or conservative analysis that does not assume a consistent rate of decline throughout the study period the number of participants would not be reduced.
• Two-stage design: The purpose of this design is to speed up the trial process by combining two drug development stages into one study.     
• More flexible entry criteria:  Byar et al (1990) argues that if treatments are found to be effective in clinical trials are likely to be offered to most patients, most patients should be eligible to enter the trials and the exclusion criteria should be systematically relaxed in order to reach this goal.  The reason clinical trials have restrictive entry is so treatment effects can be measured more precisely.  However using a method known as stratification you can analyze treatment effect based on subgroups (e.g. familial ALS versus sporadic ALS, bulbar versus limb-onset ALS).  This analysis becomes more robust with larger number of participants.        

Albert Einstein once said, “A system is only as good as its design.”  When we think about clinical trials there is no perfect study or ‘gold standard.’  Each available study design has its pros and cons.  It usually comes down to a calculation of what errors are researchers willing to accept at what cost. 

In statistics and epidemiology classes we learn that the higher your sample size or number of participants in your study, the less error or study bias you will have.  Each person you include in a study however increases the overall cost.  This is why most companies, particularly start ups have the goal of including the least number of participants at the cost of statistical power.  That is, studies with small numbers lose the ability to say with greater accuracy whether or not an effect they are seeing is true.  This is why drugs might appear safe and effective in Phase 1 and 2 trials, but bomb in Phase 3.

Now is the time to reconsider clinical trial designs for people with ALS.  The ALS Association is looking to put together a guidance document for the FDA on among many things, clinical trial design. 

Tell the U.S. FDA and industry that you want more options to try experimental drugs and faster clinical trial processes through futility designs in Phase 1, two-stage designs in Phase I/Phase 2 and Phase 2/Phase 3, relaxed entry criteria, increased sample size, and lead-in designs.  Ask policymakers to increase funding and work with industry to eliminate barriers to increasing sample sizes.    

        

References

Byar et al (1990).  Design Considerations for AIDS Trials.  New England Journal of Medicine, 323(19), 1343-1347.

Schoenfeld and Cudkowicz (2008).  Design of Phase II ALS clinical trials.  Amylotrophic Lateral Sclerosis, 9: 16-23.

Health Literacy Best Practices Needed in Clinical Trials Search Engines

Have you ever spent hours on government websites looking for health information or their policies and procedures, or simply left out of frustration?  Have you ever gone to a clinical trial search engine site trying to find experimental drugs and therapies to try, or compare the different options but felt overwhelmed?  You’re not alone.  Clearly, most clinical trial search engines are not patient-focused.  Yet when we ask our healthcare providers for more information on clinical trials, they always point us to the search engines.  The problem is that these clinical trial search engines are not written or designed with health literacy in mind.         

Health literacy is the ability to access, understand, and use health information to make decisions.  It doesn’t necessarily have to do with someone’s ability to read or their education, but whether or not health information is relatively easy to find, accessible to those with visual or hearing impairments or other disabilities, and written in plain language.  Many government websites have cluttered website layouts, too small of a font size (10-point), are difficult to navigate and find the information you need, and are written with lots of medical and scientific jargon.

Studies have shown that health literacy is linked to increased emergency room visits and hospitalizations, people being able to correctly take their medications, people following up on medical appointments, being an active participant in their health care such as self-care and preventive health screenings, and participation in clinical trials.  It’s no wonder, when you consider how the common clinical trial search engine is designed and its content.  They may be sufficient for a doctor or clinical researcher, but are far from helpful for the person with an actual disease or condition or their caregivers.  The search engines seemingly rely on the fact that your doctor or a different health care professional will help the patient and their family access the information on the clinical trials sites.

One such example is www.clinicaltrials.gov.  Over the years, this National Institutes of Health administered site has improved with the addition of a table showing you the course of action for those assigned to the treatment group versus placebo or control group.  However a lot of the information is written in medical and scientific jargon.  In fact they have to devote a separate page on their website to define these terms.  Not really a health literacy best practice.  Several of the search engine hits list outcome measures, which is typically of interest to the researcher or treating doctor but not the patient.  Navigating the various trials can also be challenging.  The study titles they use are overwhelming and not all completed studies post their results or publications.  A recent study by Utami et al (2014) shows how consumers or patients have trouble navigating clinical trial search engines and what content and layout would be best suited for a patient or consumer centered search engine.   

     

In 2007, Senators Norm Coleman (R-MN) and Tom Harkin (D-IA) introduced a bill known as the Health Literacy Act, which would have provided critical funding to expand health literacy research and best practices and developed federal and state-based patient centered resource centers.  The bill, S2424 had bipartisan support, was co-sponsored by Susan Collins (R-ME) and Amy Klobuchar (D-MN), and had support or endorsement from organizations such as AARP, U.S. Chamber of Commerce, America’s Health Insurance Plans (AHIP), National Health Council, Institute of Medicine (IOM) Roundtable of Health Literacy, American Medical Association (AMA), Institute for Healthcare Advancement (IHA), etc.  Unfortunately it stalled in Senate and never was passed.

In 2010 three major initiatives were put in place to try to address health literacy.  It was a major step forward but did not have the major funding and widespread impact that the Health Literacy Act would have delivered towards improved consumer health information.    

1.      The Affordable Care Act directly and indirectly addressed health literacy by incorporating health literacy into professional training (section 5301) and streamlined procedures for enrollment into Medicaid, the Children’s Health Insurance Program, and the state-based insurance exchanges (section 1413) (Koh et al, 2012).

2.      National Action Plan to Improve Health Literacy, unifies health literacy goals and strategies for the country and is based on the following two principles:  a. All people have the right to health information that helps them make informed decisions and b. Health services should be delivered in ways that are understandable and lead to health, longevity, and good quality of life (Koh et al, 2012).  

3.      Plain Language Writing Act of 2010 (PL 111-274): Purpose of this Act is to improve the effectiveness and accountability of Federal agencies to the public by promoting clear Government communication that the public can understand and use.

Predating these efforts was a 1998 Amendment to the Rehabilitation Act, which requires federal agencies to make electronic and information technology accessible to people with disabilities.  Known simply as Accessibility or Section 508 Compliance, everyone must be able to view online information including documents, websites, and videos regardless of their disability.  Web Content Accessibility Guidelines were established that enables content on the Web to be accessible to a wider range of people with disabilities, including blindness and low vision, deafness and hearing loss, learning disabilities, cognitive limitations, limited movement, speech disabilities, photosensitivity and combinations of these.  Some examples of how this is implemented include video captions and web materials that are compatible with assistive technologies such as screen-readers.  Although this had been in law for over a decade, it had not been implemented to its full extent resulting in lawsuits. 

So what needs to happen?  People with ALS, their caregivers, and advocates need to demand that clinical trial search engines be health literate.  They need to implement consumer or patient-focused website design, plain language, numeracy, and accessibility standards.  Clinicaltrials.gov is one of the major search engines, so let’s start there.  Ask policymakers to reintroduce the National Health Literacy Act to provide real funding towards revamping ClinicalTrials.gov and making other health information accessible.    

References

Koh HK; Berwick DM; Clancy CM; Bauer C; Brach C; Harris LM; Zerhusen EG (2012).  New Federal Policy Initiatives to Boost Health Literacy Can Help the Nation Move Beyond The Cycle of Costly ‘Crisis Care.’ 

Senator Norm Coleman’s Office.  Coleman, Harkin Introduce National Health Literacy Act.  [Press Release], December 6, 2007.  Washington, DC.  http://votesmart.org/public-statement/309745/coleman-harkin-introduce-national-health-literacy-act#.VU5LDiFViko

Utami D, Bickmore TW, Barry B, Paasche-Orlow MK (2014).  Health Literacy and Usability of Clinical Trial Search Engines.  Journal of Health Communication: International Perspectives, 19: sup2, 190-204.

What ALS Can Learn from the Cancer Experience: The American Public Can be a Powerful Change Agent

“You must be the change you wish to see in the world.” - Mahatma Gandhi  

The Cancer Experience teaches us that the American Public can be a powerful change agent.  Recall, Dr. Slayman from the UCLA Medical Center who became a powerful change agent when he convinced Genentech (San Francisco, CA, USA) to fill out a clinical trial application for the cancer therapy, Herceptin (see post: What ALS Can Learn from the Cancer Experience: Identify and Support Champions and Change Agents)?  Well the story doesn’t end there.   

Before Genentech could start Phase 2 clinical trials, its Phase 1 success was highly publicized in the media.  Soon, Genentech phone lines and mailboxes were inundated with calls and letters from women wanting the drug under Expanded Access.  The company flat out refused.  They wanted to focus efforts on enrolling people for the clinical trials and were nervous that widespread access would halt the clinical trial process.

A young gynecologist by the name of Marti Nelson had recurrent breast cancer and wanted to participate in the Herceptin clinical trials, but was repeatedly denied.  In response to her death in 1994, thousands of activists stormed Genentech.  They decided to hold a funeral procession for Marti Nelson right in front of Genentech headquarters.  They chained themselves to the doors, and pounded on the doors for Expanded Access.  All in plain view of the media.             

Pressure built and in 1995, Genentech arranged talks with the breast cancer advocates.  The company decided to provide Herceptin to small numbers of women outside of clinical trial on a basis of a Drug Lottery.  A true success story for cancer advocates. 

The Ice Bucket Challenge, Steve Gleason Act of 2015, and policy change advocates who will be in Washington D.C. this May is an astounding testament to the power of the ALS Community.  Now is the time to think BIG, and demand policy form that will result in treatment options for those suffering with ALS who do not qualify to participate in clinical trials.  Thanks to the HIV and Cancer Movements, the U.S. FDA already has programs in place to fast-track and offer treatments outside of clinical trial.  The U.S. FDA approves nearly all applications for Expanded Access.  Now’s the time to advocate for the Marti Nelsons of the ALS Community.  Demand that your policy makers remove barriers and provide incentives to the companies to offer Group and Widespread Expanded Access Programs for promising experimental drugs, therapies, and devices.

What ALS Can Learn from the Cancer Experience: Bypassing Clinical Trials, A Cautionary Tale

Dr. Siddhartha Mukherjee’s, author of the book, The Emperor of all Maladies: A Biography of Cancer in the PBS Documentary said, “Medicine being the most humane science…sometimes scientists are caught doing inhumane things which is denying experimental drugs.  However, putting a drug on the market too early has had historically devastating events.” 

What Mukherjee is referring to is the consequences of releasing an experimental drug or treatment via Accerlated Access before Phase 3 clinical trials have been undertaken.  An example of this is the STAMP treatment for breast cancer in the 1980s and 1990s.

In 1983, Dr. Peters and Dr. Frei started breast cancer clinical trials on a new therapy previously shown to have some success at treating childhood leukemia, known as the Solid Tumor Autologous Marrow Program (STAMP).  STAMP involved extracting bone marrow from the participant and freezing it, then wiping out their cancer with extremely high doses of chemotherapy, and injecting the bone marrow back into the person so that the high-dose chemotherapy wouldn’t kill them.  Promising success in Phase 1 and 2 clinical trials with breast cancer patients encouraged women who could not participate in the trials to seek accelerated approval of the treatment.  Soon 30,000 some women received access to the experimental therapy between 1985 and 1998 at the cost of millions of dollars.  The study could not recruit people for the Phase 3 clinical trials because no one wanted to be in the control group.  About 1 in 5 women died from the treatment and it was later shown that the higher dose of chemotherapy was not any more successful than the lower doses in improving women’s survival.  And in fact there was a higher chance of death due to the bone marrow implants.  Those who did survive the procedure suffered long term cognitive problems such as short term memory loss.     

    

Some of you might still be asking yourselves, so what’s the big deal?  The women at least got a chance to try something?  The big deal is that an experimental treatment that has not gone through the full round of required clinical trials carries a higher risk of actually shortening the person’s life if not killing them.  Perhaps someone who is near the tail end of their disease is willing to take this risk, but what if you are someone who is early on in their disease?  By foregoing clinical trials you risk shortened lifespan, death, and the right to try other treatments that might become available.  That’s right, clinical trials have strict inclusion and exclusion criteria.  Meaning, in order for the researchers to know without a doubt that their treatment is having an effect, they cannot allow anyone into the trial that has taken other experimental drugs.  Moreover, what if a drug is approved for Accelerated Access and a large number of people start taking the drug and suddenly have major toxic reactions or die.  Even if this is unrelated to the treatment itself, such an event might trigger the FDA to remove the treatment from the market altogether…that’s it.  A possible beneficial treatment to some people with ALS will never reach them.        

  

I’m not saying we should not seek treatments through Accelerated Access period. I’m simply saying there is a time and place.  The U.S. FDA Evaluation team is in place to insure consumer safety.  If companies can satisfy their requirements that show scientifically that their treatment warrants Accelerated Access based on evidence that is safe and efficacious than this is a good thing.  If not, we should consider other options for treatments outside clinical trials such as Widespread and Group Expanded Access, which is politically more kosher with the U.S. FDA and doesn’t hinder the clinical trial process. 

On May 10, let’s ask our policy-makers to work with ALS advocates, pharmaceutical and biotechnology companies, the Centers for Medicare and Medicaid Services and the U.S. FDA to remove barriers for companies to offer Expanded Access to People with ALS.