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Letter to the 45th President of the United States

Date: September 14, 2016

Subject: Strategic Management Principles

Introduction.

By the time you are sworn into office, both the 43rd and 44th Presidents will have left the office with more than 60% of the public thinking the country is on the wrong track. Coincidentally, the partisanship in Washington is at all-time highs and there is little follow-through on the heavy lifting needed to get things done.

To turn the tide, the next President needs to stake out a focused strategy that feels right for most people and one that is supported by an achievable implementation plan.

In trying to identify the proper focus for the new Administration, it doesn’t take a genius to realize that U.S. citizens want to be better off, healthier and safer than they are today.  These basic desires apply to the rich and poor, the healthy and the sick and Republicans and Democrats.

Tying these simple concepts into strategic objectives can take many paths, but a simple and clear way to lay out the overall strategic imperatives for the new Administration is as follows:

  • Improve the financial well-being of the country and its citizens
  • Improve the health and healthcare of U.S. citizens
  • Establish and implement a global plan to curb terrorism

The strategic plan to implement these objectives should be within the purview of the government’s scope of responsibilities, achievable and impactful when implemented.  And to the horror of the political operatives, it should not purport to fulfill all or most of the promises made on the campaign trial.

The Economy First.

The first major strategic objective of the new President should relate to the economic well-being of the country, which also is the engine that helps to solve many social issues. Historically, the federal government has sought full employment and stable prices. Today, the focus needs to be on job creation in the face of an aging population while, at the same time, taming a growing national debt.

Economic growth is a fickle endeavor.  It depends on investment, which, in turn, depends on human emotions such as fear and greed. These emotions can be contagious so that positive or negative events often tend to elicit herd behavior.

Today, U.S.-based companies are sitting on $1.5 trillion in cash that is not being invested in job producing projects. In fact, about $500 billion of this cash will be used to buy back company shares, which produces no value to society.

The President’s tool kit for addressing the economy is limited mainly to fiscal policy, through which the government determines the appropriate level of taxes and spending.

While various approaches to fiscal policy are advocated with great fervor, there is no unambiguous support for economic stimulus programs or tax cuts standing on their own.

What is more important for eliciting increased investment is for the President and Administration to instill confidence in the markets. The single biggest factor that can install confidence is control over the federal deficit by showing declines each year in the annual budget deficit, ultimately leading to a balanced budget.

To be effective, this general strategy needs to be coupled with a series of targeted programs at problem areas such as job retraining, infrastructure deployment, and tax incentives.  For example, the President could pursue a 0% capital gain tax for all standalone investments in the first 18 months of his or her term that produces jobs.  Alternatively, the President could advocate the doubling of the salary of all new hires in the next twelve months for purposes of calculating the hiring company’s federal income tax deductions.

Finally, the federal government represents about 20% of the economy and needs to operate more efficiently.  The next President should establish a new permanent position of Chief Operating Officer as a non-political appointee with dotted line responsibilities for overseeing all of the implementation (as opposed to policy) responsibilities in the federal government. For example, this person would be responsible for ensuring that proper hiring practices, training, reviews, correction actions, reporting, etc. are in place in each organization to ensure efficient operations.

Healthcare Second.

In looking at the numbers, the next best place for the next President to have a large, meaningful, and long-term impact is the healthcare industry.  Significant improvements are achievable considering that the citizens of most other advanced countries have better health and lower healthcare expenses per capita than in the United States.

To come up with a plan to improve the health of people and reduce the costs of healthcare, a basic understanding of the industry is required.

In broad terms, the cost of healthcare in the United States in 2014 was approximately $3.0 trillion (or $9,500/person), including:

  • 32% for hospital care
  • 20% for physician and clinical services
  • 10% for prescription drugs
  • 5% for nursing care facilities and continuing care retirement communities

When looking for causation for these healthcare expenditures, there are many large targets:

Disease Population Affected Impact
Asthma 26 million 11 million missed school days; 2 million emergency visits
Alzheimer’s 5 million Debilitating illness leading to need for increasing care and to early death
Diabetes 26 million 37 million medical visits per year
Epilepsy 3 million Seizures leading to lost productivity
Heart disease 27 million 12 million annual medical visits; 2 million annual outpatient department visits; 600,000 annual deaths
Cancer 15 million 90% of the 600,000 deaths per year attributable to metastasis; 1.6 million new cases per year

Taken together, chronic diseases cause 7 of every 10 deaths in America. Moreover, about 25% of people with chronic diseases have some type of activity limitation such as needing help with dressing or bathing or being restricted from work or attending school.

By any measure, chronic diseases take a heavy toll on the nation’s health and wealth. For example, heart disease and stroke are estimated to cost over $430 billion per year. Diabetes costs are estimated to be about $175 billion per year.  Alzheimer’s is estimated to add about $150 billion per year. And cancer adds over $200 billion per year. In total, over 50% of the $3 trillion spent on health care each year is attributable to chronic diseases.

When the issue is looked at in this light, two questions come to mind:  1) how can these diseases be better managed (or prevented) and 2) what is holding up progress?

In terms of the hold up for cures, drug discovery and implementation is not an efficient process.

For example:

1) There are no recognized champions or leaders in industry or the government who are laying out a strategic vision for an overall approach to each chronic illness. That is, no one “owns” the relevant problems nor is there a coordinated plan of attack.

2) The resources devoted to specific illnesses generally are not coordinated nor prioritized along the path of the strategic vision (or any specific path).

3) Faculty at medical centers and research institutions around the country are expected to publish in scholarly journals, not to participate in industry-wide joint planning or development on a particular approach or objective.

4) There are no recurring report cards for the costs of care by disease, particularly categorized by stage of illness, age of patient, etc.

5) There are no recurring report cards for the performance outcomes of treatments, including how performance relates to the cost of treatment.

6) There are no recognized benchmarks or objectives for consumer education, prevention, treatment, care or the cost of treating the various illnesses.

7) There is no clear objective or objectives for management of the disease whether the statistic relates to the overall incidence, the 5 or 10-year survival rates, etc.

Even if the industry were more efficient, the process for approving drugs at the FDA is fraught with long delays and the imposition of excessive costs. For example, the average drug takes 12-15 years to achieve FDA approval at a cost well over $1 billion.

Despite the dismal record of drug discovery over the last 50 years especially when compared to other endeavors, there are encouraging signs.  First, some organizations have stepped up into leadership positions such as the Michael J. Fox Foundation for Parkinson’s disease and The Basser Center at Penn’s Abramson Cancer Center for hereditary breast cancer.

Second, technology has moved forward so that “Big Data” capabilities enable the crunching of tremendous amounts of information on people regarding their genes, the environment, exercise, diet, drugs, etc. to more quickly identify causation and cures.

Given the present circumstances, the next President can take three actions to dramatically affect the direction of healthcare in the United States.

First, the priorities for healthcare must be clearly set on the proper targets.  For example, a “moon shot” on cancer is not the way to go.  Nor is a generic approach on Precision Medicine Initiatives.

Rather, specific types of cancer or specific illnesses such as Alzheimer’s disease is the proper way to set priorities and organize resources. Additionally, Precision Medicine Initiatives should be pursued in the context of a market need as opposed to a solution in search of a problem.

Second, the new Administration in concert with industry and academia should establish separate organizations to develop and lead the overall plan of care for each major chronic illness, including the associated drug discovery efforts.  This organization would be responsible for the overall approach to treating each specific disease, including tracking the resources spent on pursuing cures and what additional avenues should be pursued, among other things.

For example, the President could establish a new Cabinet level position along with several Undersecretaries, each of whom would be responsible for healthcare improvement on a specific major chronic illness.  These Undersecretaries would be responsible for the overall plan to address the disease whether it be reporting, training, diet, estimating funds necessary for research, identifying specific paths for a cure, etc. The Undersecretaries in turn could establish a virtual organization of government employees, members from private industry and academia to provide guidance and drive focus and resources on the best approaches to care.

Third, the FDA’s drug approval process should be examined and modified as appropriate for each chronic illness.  Today, new treatments for various illnesses get fit into the same approval straight-jacket.  Rather, under the new approach, the leader assigned to each of the top chronic illnesses would determine the proper role for the FDA in each research initiative.  For example, while final FDA approval would be required for new treatments, the leader would determine the appropriate scope of FDA involvement in pre-clinical research and/or the early stages of clinical trials, if any.

In short, the next President can and should set priorities, organize resources and modify regulatory procedures in the healthcare industry to have a major and lasting impact on the nation’s health and its cost for healthcare.

Conversely, there is no need for the President to get bogged down in the issue of health care insurance.  From a policy standpoint, the issues here revolve around who can and cannot afford insurance, the subsidies paid by government for insurance, and how the subsidies will get funded.  The best way for the federal government to address these issues over the long-term is to get healthcare costs down and get personal income up, as outlined above.

The National Defense Third.

The third major strategic objective for the next President should relate to the national defense.  This area requires the greatest change in organizational structure and culture and therefore requires the most personal involvement by the President.

As background, the military budget of the United States military was roughly $600 billion in 2015. This includes war spending, weapons spending, Department of Defense and other Pentagon-related spending and international military assistance.

Total military spending also includes about $16 billion in military expenses for the Department of Homeland Security (DHS), which was established in 2002. This department also gets funds that are not designated as military spending, including funding for law enforcement, border control, and other pseudo-military expenses. The non-military Department of Homeland Security funding was about an additional $43 billion in fiscal year 2015.

The Department of Homeland Security has about of 230,000 employees and 22 departments including TSA, Customs and Border Protection, Immigration and Customs Enforcement, U.S. Citizenship and Immigration Services, FEMA, the Coast Guard and the Secret Service.

Political candidates often promote and protect military budgets.  However, much of the military spending emanates from programs when nation-states represented the biggest threats to the United States.  Today, terrorism, in coordination with rogue nations (such as Iran and North Korea), is the biggest threat.

To be effective, the government would need very different organizations, resources, objectives and plans for dealing with nation-states versus terrorism.  The mentality and culture of the counter-terrorism community should be one of aggressive and proactive behavior, whereas the approach for nation-states should be measured and defensive in nature.

Additionally, the consultation and coordination with other countries would be different for addressing nation-states and terrorism.  Counter-terrorism requires a real-time coordination at an operational level with many countries, including Russia and China.  To be effective, the relationships and coordination of counter-terrorism groups between countries should be very different from the relationships between the diplomats of those countries.

For addressing the nation’s defense against nation-states, the long-standing apparatus of the State Department and the Department of Defense is more than sufficient for the task. However, given today’s realities, the objective for the military to be able to conduct two wars simultaneously is no longer a strategic necessity.  With this change in objectives, military spending as presently constituted would be substantially above what is needed to defend the country against nation-states and should be cut accordingly.

By the same token, the counter-terrorism budget is significantly understated and the function is buried within DHS.  The next President should break out counter-terrorism and make it a Cabinet-level responsibility, including handling all policy matters for addressing rogue nations in the fight against terrorism.

Under such an approach, the warnings of the next 9/11 attempt would be much more likely to be identified – and acted upon — before terror strikes.  For example, the daily terrorist briefing reports should be going to someone who is inclined to act upon them – quickly.

Summary and Conclusion.

In short, the next President should not try to be all things to all people. Nor should he or she promote a seemingly endless laundry list of “to do’s” in the State of the Union address as a sop to the political operatives.

Rather, the next President should lay out a short list of overarching strategic imperatives and establish the plans, organizational structures and resources needed to drive the implementation of those imperatives.

After that, the President’s role would be to make the approach feel right for everybody and to hold government executives accountable for making it happen.

If the President were to follow these simple basic leadership and management principles, the nation as a whole would be wealthier, healthier and safer.  That outcome would coincide with most people thinking the country is on the right track, once again.  There would no need for the President to curry favor from the political operatives and partisanship would be left for the losers.

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Petition to the FDA on Precision Medicine Initiatives

                           EXECUTIVE SUMMARY

 

In his 2015 State of the Union address, President Obama announced the launch of the Precision Medicine initiative “to revolutionize how we improve health and treat disease”. The White House subsequently specified that the Initiative “will include reviewing the current regulatory landscape to determine whether changes are needed to support the development of this new research and care model”. White House Fact Sheet: January 30, 2015.

On September 17, 2015, under the leadership of the NIH Director, the Precision Medicine Initiative Working Group recommended the creation of a national research participant group (a cohort) that would lead to trials of precision therapies, among other things. The Working Group’s recommendations were adopted by the Director. The cohort is expected to have over one million participants within four years, according to the NIH News Release issued that same day.

To support the progress of the Precision Medicine Initiative, the FDA adopted its precisionFDAprogram that consists of a research and development portal that would allow community members to test, pilot, and validate existing and new bioinformatics approaches for processing the vast amount of genomic data that is collected using Next Generation Sequencing technology. See: www.precision.fda.gov.

As with other new drug initiatives, Precision Medicine Initiatives require FDA approval before they can be marketed to the public. The FDA utilizes the Center for Drug Evaluation and Research (CDER) to fulfill its responsibilities in this regard.

The FDA’s CDER procedures are such that new drugs have typically taken 12-15 years to be approved at an average cost per approved drug of over $1 billion. The FDA approves about 25 new drugs a year on average. See, e.g., www.FDAReview.org, The Drug Development and Approval Process (2016).

Without modifications of the CDER’s procedures for application to Precision Medicine Initiatives, it is likely that tangible results from the President’s program will take more than 15 years to reach the public – and will do so only if the precision initiatives targeted to small groups of people can withstand the cost burden of FDA regulations on a per-person basis (which is unlikely).

Accordingly, this Petition requests the FDA to issue an Advance Notice of Proposed Rulemaking to address what modifications, if any, are appropriate to the FDA’s approval process for new drugs and treatments emanating from Precision Medicine Initiatives.

The issues raised by this Petition include:

a) Can any therapies emanating from the Precision Medicine Initiative be introduced into interstate commerce without FDA approval? Does the existing legislation provide the FDA with flexibility to tailor its regulations to fit the circumstances of precision therapies or to create partial or full exemptions of the regulations for certain precision medicines?

b) If the FDA were to adopt a separate classification for Precision Medicine Initiatives, what should the inclusion criteria be for this class?

c) Can and should the FDA regulate PMI treatments emanating from the NIH cohort differently than those emanating from non-governmental run cohorts?

d) Can the typical Precision Medicine treatment sustain the high costs and resultant high per-person prices that would result from the application of the existing FDA regulations to a therapy with a very small target market?

e) What regulatory alternatives exist to the current drug approval process that would provide increased incentive for private capital formation to fund R&D for Precision Medicine Initiatives without compromising consumer safety?

f) What are the risks and rewards of different regulatory approaches for Precision Medicine Initiatives?

g) Should the FDA develop, maintain and publish a scorecard that keeps track and provides annual updates of the progress of all Precision Medicine Initiatives (both private and public)?

The national cohort under NIH will take several years to build before it will begin to show signs of progress. Nevertheless, the time for action on this Petition is now because there are many more private precision medicine research initiatives that would proceed with the certainty of a well-functioning regulatory framework.

I. Action Requested

On February 11, 2016, I wrote to the FDA to ascertain whether it had started or planned any rulemakings addressing Precision Medicine Initiatives. I did not receive a response.

This Petition requests the FDA to issue a comprehensive Advance Notice of Proposed Rulemaking seeking legal, economic and scientific input on how best to analyze and approve, as appropriate, new Precision Medicine Initiatives.

This action is warranted now because much greater efforts would be put in place for Precision Medicine Initiatives in the private sector with the proper regulatory procedures in place.

The Petition seeks to have the FDA lay out in fine detail the entirety of its drug approval process so that commenters can provide estimates for the impact of the various FDA procedures on the cost, risk and delay of new therapies as well as the benefits flowing to the public from the regulations.

The Petition also sets out alternative regulatory procedures for Precision Medicine Initiatives so that the FDA can seek informed comment on various approaches as the research community seeks to pivot from R&D focused on blockbuster drugs to therapies focused on personalized care.

II. Statement of Factual Grounds for the Requested Action

Title 21 of the Code of Federal Regulations confers upon the FDA the responsibility to ensure that drugs are safe and effective before being marketed to the public.

This responsibility confers huge benefits and costs upon society.

The costs can be identified as direct and indirect. Direct costs would address the out-of-pocket costs to gain regulatory approval.

For example, economist Joe Dimasi of the Tufts Center for the Study of Drug Development estimates the out-of-pocket costs to get FDA approval to be approximately $1.4 billion per drug. This estimate is roughly consistent with the total spending for drug research divided by the number of approved drugs over a specified number of years. See, e.g., The High Cost of Inventing New Drugs – and of Not Inventing Them”, The Institute for Policy Innovation (April 16, 2015).

Indirect costs would include the loss of benefits to patients from unnecessary regulatory delay.

The amount of time needed to advance varies widely by initiative, but it typically takes 1-6 years for preclinical research, 6-11 years for clinical trials and up to 2 years for review and approval. The typical cycle involves 12-15 years of development before approval.

Another form of indirect costs includes the loss of efficacious discoveries that never make it through the process. Researchers refer to this syndrome as the “Valley of Death” because the risk, cost and delay of the FDA drug approval process makes it impossible for them to raise private capital to pursue the research.

On the other side of the ledger, the benefits of FDA regulatory procedures include the cessation of death and prevention of other significant adverse events in clinical trials and subsequently in the public market. Similarly, if inefficacious drugs can be kept off of the market, this represents a direct benefit to the public in terms of cost avoidance.

The two most widely quoted examples that demonstrate these benefits relate to Sulfanilamide and Thalidomide.

In 1937, a Massengill, a Tennessee drug company, began to market a liquid drug called Elixir Sulfanilamide.  The solvent in this drug was a highly toxic variant of antifreeze; as a result, over 100 people died from taking this drug.

In the 1960’s, Thalidomide, a sedative that was marketed to combat the symptoms associated with morning sickness in pregnant women, caused birth deformities in thousands of babies throughout Europe.

The value of human life is a delicate matter, but for purposes of public policy, the FDA has used a figure of $7.9 million in cases related to cigarette smoking. For purposes of the analysis raised by this Petition, the FDA should also establish monetary values for: 1) avoiding significant adverse effects (other than death) on a per-person basis, and 2) the delay of cures on a per-person basis. The FDA could use benchmark values of $1 to $4 million for these events, depending on the circumstances.

For example, the FDA has approved MRI-guided focused ultrasound for treating cancer. Therefore, for purposes of using the same technology to treat tremors, the FDA’s focuses on efficacy rather than safety. For purposes of illustration, if the FDA were to add a rigorous safety component to the clinical trials that use this technology for tremors, the net benefit of that component could be estimated to be:

Net gain/loss = (($6.9M x number of lives saved) + ($4M x the number of significant adverse effects avoided)) minus ($Y x probability of approval x number of likely recipients), where Y is set based on the expected length of the delay. For example, Y might be set at $1M if the added delay was projected to be two years.

Similar formulae can be used to determine the net gain or loss for every variable in the FDA drug approval process identified in Section III as well as the alternative approaches identified in Section V.

By using such a framework, the FDA will be able to identify the optimal drug approval procedures for Precision Medicine Initiatives.

III. The FDA Should Detail the Parameters, Activities and Results of its Drug Approval Process as Part of the Advance Notice of Proposed Rulemaking

The Precision Medicines Initiative is made possible by the emergence of “Big Data”.  Big Data allows the collection, storage and computation of massive amounts of information on an economic basis. As such, it fundamentally changes the approach to experimental design. Today, researchers can afford to collect virtually unlimited amounts of data and search for significant patterns in the data.

The same principle applies to regulatory procedures. With detailed specifications of CDER’s activities on a relatively large sample of drug initiatives along with the associated results, researchers and the FDA will be able to better isolate and discern how each process produces benefits and costs to the public.

The FDA has a variety of classifications along with different procedures that it uses for new drugs including Fast-Track, Breakthrough, Priority Review and Accelerated Approval. It also tracks whether the drugs are First-In-Class and/or targeted to fewer than 200,000 recipients (i.e., so-called Orphan Drugs).

Its principal tools are issuing guidelines for good laboratory practices, conducting quality assurance oversight of pre-clinical research and thorough examination of all data submitted for each phase of the clinical trials. It also uses a series of Advisory Committees to help in its deliberations and relies heavily on the recommendations of Institutional Review Boards for final decisions.

The FDA implements its mandate by examining the outputs of research affecting toxicology (pre-clinical), safety (Phases I-III), dosing (Phase II), efficacy (Phase II-III) and side effects (Phase III).

The FDA procedures also vary depending upon whether a drug was approved for another application. In these cases, the FDA’s focus is efficacy with a diminished focus on safety.

The FDA’s procedures have also varied over time, principally as a result of new legislation.

For example, the length of time for the FDA approvals began increasing after the 1962 legislative amendments; from about 1 year to 3 years by the end of the decade and then up to 10 years in the 1970’s.

Similarly, the cost of research and development per approved drug has increased from $100m in 1975 to $300 million in 1987 to over $1 billion more recently.

The various procedures employed by the FDA over time have produced different results. The results of greatest import include: 1) the probability of proceeding from each stage of research, 2) the time required for each phase, 3) the out-of-pocket expenses for each step in the process and 4) whether the new drug was safe and effective in the market.

Taken together, the FDA has thousands of data points of inputs and outputs to its drug approval process that, if made available to the public, would enable researchers and the FDA itself to systematically evaluate the various procedures it employs today and that it has employed over time to determine the benefits and costs of each of the tools and procedures that it has used.

For example, the data might show that complex, novel discoveries attract more FDA attention in pre-clinical research and when that occurs the probability of success in clinical research goes up (or down) by an average of x%. Conversely, the data might show that when a therapy has been approved for other applications, the time to market decreases by Y years (thereby isolating one of the costs of the safety component of the FDA’s review).

Armed with information to correlate regulatory actions and the associated outcomes, the FDA will be in a position to determine the optimal procedures for addressing the approval process for Precision Medicine Initiatives.

Accordingly, this Petition requests that the FDA include in the requested Advance Notice of Proposed Rulemaking detailed information in tabular form providing the classification(s), the various tools employed, and the outputs for those classifications and tools for a wide variety of individual discoveries and drugs.

In particular, the FDA should specify this information for such wide-ranging research as polio/virus vaccines to treat cancer, stem cells to treat Parkinson’s disease, and various research initiatives for metastatic cancer and Alzheimer’s disease, among others, including discoveries (and failures) in earlier times.

IV. The FDA Should Solicit Comments on the Key Issues Raised by the Emergence of Precision Medicine Initiatives

The FDA should seek comment on the following issues:

A. Definition of Precision Medicine Initiatives

The FDA should define the drugs and discoveries that fall into the classification of Precision Medicine Therapies. For example, the FDA uses the classification “Orphan Drugs” for therapies with a population target of less than 200,000.

In kicking off the PMI, President Obama noted that Precision Medicine Initiatives will be developed on an individualized basis based on a person’s genome sequence, metabolomics, microbiome and other specific data about the patient.

Therefore, one definition of PMI could be any research initiative that utilizes genetic information in combination with other personal data to treat health conditions. Under this approach, research for diseases such the cancer resulting from a BRCA mutation would be considered a PMI.

Alternatively, the PMI definition could follow the approach of the “Orphan Drugs” classification and include all research with a target population of less than a specific number of patients (presumably less than 200,000).

Thirdly, the FDA could combine the two approaches to create the definition of Precision Medicine Initiatives based on target size and the inclusion of genetic information.

Finally, the FDA could use one (or more) of its existing classifications for Precision Medicine Initiatives.

To provide an example of the definitional challenge for PMIs, thirteen gene mutations associated with Parkinson’s disease (PD) have been identified. In some cases, the genetic mutations are rare such as with the alpha-synuclein gene. In other cases, a mutation might lead to PD and additional disorders such as Lewy body dementia. To compound the complexity, the first disorder may affect a population above the target threshold and the second disorder may be below the target threshold. Moreover, as more genetic and personal data are gathered, the size of the target population for specific treatments will get smaller over time. For example, going back to the BRCA mutation example above, today BRCA mutations are categorized as Triple Negative. However, on-going research is likely to show that BRCA-related Triple Negative cancer behaves very differently than non-BRCA Triple Negative cancer and therefore deserves a separate categorization.

B. Legal Issues

The FDA should seek comment on whether any therapies emanating from the Precision Medicine Initiative can be introduced into interstate commerce without FDA approval.

The emergence of “Big Data” capabilities has brought a class of new pioneers to health care, namely those from Silicon Valley. These new entrants have no experience with regulatory procedures. In many instances, these entrants have the attitude of the lead actor in the movie Dallas Buyer’s Club” (2013), namely that they will find a cure and the FDA will not be able to stop them once the cure takes hold in the market. Such a confrontation can be avoided with the proactive approach requested by this Petition and the “market” will operate more efficiently.

Another legal issue that the FDA should seek comment relates whether the existing legislation provides the FDA with flexibility to tailor its regulations to fit the circumstances of precision therapies and/or to create partial or full exemptions of the regulations for certain precision medicines.

The FDA should also seek comment as to whether it can (and should) regulate treatments emanating from the NIH cohort differently than those emanating from non-governmental research cohorts.

C. The Economics of Precision Medicine Initiatives

The FDA should seek comment on whether the typical Precision Medicine treatment can sustain the high costs and resultant high per-person prices that would result from the application of the existing FDA regulations to a therapy with a very small target market.

In the same vein, the FDA should seek comment as to whether the current drug approval process has inadvertently devolved into a system that accommodates mostly expensive, blockbuster drugs, while keeping low-cost, targeted, competitive alternatives such as PMIs from entering the market.

D. Reporting

Management science tells us that when improvement is desired, leaders must focus on the relevant item(s) that needs improvement, develop a strategic plan to address these items, organize the resources necessary to execute the plan, track progress against the plan’s objectives and make adjustments to the plan when needed.

The FDA should seek comment on whether it should – at a minimum – develop, maintain and publish a scorecard that keeps track and provides annual updates of progress of all Precision Medicine Initiatives (both private and public). For example, such reporting could be used to signal the need for mid-course corrections if progress deviates significantly from expectations.

V. The FDA Should Seek Comments on Alternative Drug Approval Processes for Precision Medicine Initiatives

The FDA should solicit comment on a wide range of alternative drug approval processes, including:

A. The Status Quo

The status quo is the benchmark by which any changes to the FDA’s drug approval procedures for Precision Medicine Initiatives should be measured.

With comments on the ANPRM, the FDA will receive a good indication of the likely impact of applying the current regulations to Precision Medicine Initiatives. With this information, the FDA will be able to estimate the net gain to society from applying the status quo regulations in terms of the formulas identified in Section II. This estimate should be the benchmark against which alternative drug approval processes are measured.

B. Partial Exemptions

The FDA could choose to eliminate some of its procedures for PMI. For example, in the “Death of Cancer” (2015), Vincent DeVita (former Director of the National Cancer Institute) argues that the FDA should delegate all authority for early clinical trials (Phases I and II) to cancer centers.

As a general matter, the FDA is involved in preclinical research as well as all three Phases of clinical research. The FDA should seek comment on which, if any, of these activities should be exempt from regulation for Precision Medicine Initiatives. Commenters should also be encouraged to translate their recommendations into tangible costs and benefits to be compared to those emanating from the status quo regulatory scheme.

C. Conditional Approvals

The FDA could choose an approach for PMIs that involves surveillance only, with conditional approval after clinical trials (provided that no deaths or significant adverse results were reported in the trials).

Such an approach would rely on the fact that Title 21 does not give the FDA to regulate the practice of personalized medicine, which rests with the states and medical professional associations.

The use of conditional approvals would impose significant reporting obligations on PMIs to provide comprehensive information to personal medical providers and it would also put extensive reporting obligations on the sponsors to track performance in commerce. After a certain amount of time such as two years had passed, the conditional approval could become final, if warranted by the real-world performance as certified by personal medical providers.

D. A New Market-Based Process

The FDA should seek comment on regulations designed to improve private capital formation for research and development of Precision Medicine Initiatives targeted to small populations without compromising consumer safety.

One such approach is as follows:

i) The FDA’s role in preclinical research would be limited to surveillance.

iiEach pre-approved, qualified professional research organization filing a Phase I PMI drug application would receive a provisional license from the FDA within 60 days from the time it provided the details of its trial and put a corresponding deposit into an escrow account.

Likewise, applications for Phase II and Phase III trials would also be subject to a 60 day review cycle and would require additional funds to be deposited into an escrow account, the amount of which would be subject to the size of the trials. A sample deposit schedule follows:

Phase I – $25,000 per trial participant

Phase II – $10,000 per trial participant

Phase III – $5,000 per trial participant

The above schedule would produce escrowed deposits as follows: 

                             Number of                 Incremental                             Cumulative

                                        Participants                  Deposits                                  Deposits

Phase I                20 – 40        $0.5M – $1M                 $0.5M – $1M

Phase II           100 – 200           $1M – $2M                  $1.5M -$3M

Phase III      1000 – 3000        $5M – $15M               $6.5M – $18M

The FDA could reduce the above deposits for special considerations. Alternatively, the deposit schedule could vary according to the size of the target audience.

iii) An industry organization would be required to provide regular reports to the FDA for purposes of PMI oversight (along with the reports provided by individual research organizations with the results of each phase of its trial). This industry organization would have the authority and responsibility to audit individual trial results and to maintain a secure whistle blower system.  A reward would be paid to whistle blowers whose efforts led to the successful prosecution of fraud by a licensee.

iv) The FDA would have the authority and obligation to stop the sale of any new drug, procedure or device that it believed was unfit for human application.  If a company were found to be in violation of the FDA’s guidelines, the company would lose its license and forfeit its escrowed funds.

v) Research organizations would be required to maintain and submit relevant health statistics on patients for two years from commercial launch.  Sixty days after such filings, the FDA would issue a commercial license (if warranted by the real-world experience) and the escrowed funds would be returned.

Likewise, if the research organization voluntarily abandoned its program during development, the deposit would also be refunded.

Such an approach would place the risk, pace and costs of both pre-clinical research and clinical trials principally under the control of qualified research organizations.  The effect would be greater funding opportunities for the private sector to pursue promising research opportunities.

In addition, this approach would put the proper incentives and penalties in place to forestall the introduction of unsafe products to the public.

The FDA should request commenters to attempt to quantify the costs and benefits to consumers of such a market-based approach compared to applying the status quo regulatory approach to Precision Medicine Initiatives.

VI. Statement of Legal Grounds

This Petition is being filed pursuant to Title 21 of the Code of Federal Regulations, Sections 10.30 and 10.33.

The FDA has the power to issue an Advance Notice of Proposed Rulemaking subject to the Administrative Procedures Act and the broad discretion afforded to it by Title 21.

Since 1906, Congress has passed over 200 laws creating a framework to empower the FDA to act on behalf of the public’s health and well-being.

These laws do not provide an explicit formula for drug safety analysis or thresholds of efficacy. Rather the FDA must balance the risks and benefits in determining whether to approve a drug according to the regulations that it implements.

By the same token, the FDA cannot take away an individual’s rights under the 5th Amendment of the United States Constitution to receive state-of-the-art medical care. In this regard, the Courts have identified the relevant factors to consider for such taking, including the economic impact of the regulation, the degree to which the regulation interferes with investor-backed expectations, and the character of the government action. All of these factors are at play in the context of the President’s Precision Medicine Initiatives and the associated FDA’s regulations.

VII. Conclusion

President Obama kicked off the Precision Medicine Initiative with the promise of revolutionizing how we treat disease and improve the health of people in this country.

Unfortunately, as presently constituted, it appears that the FDA’s drug approval procedures will have the unintended effect of preventing most Precision Medicine Initiatives from legally entering interstate commerce.

Accordingly, the FDA should issue an Advance Notice of Proposed Rulemaking seeking comment on the impact of applying the FDA’s current drug approval procedures to Precision Medicine Initiations as well as soliciting thoughtful analysis of the alternative procedures.

VIII. Environmental Impact

The action requested is subject to a categorical exclusion and therefore does not require the preparation of an environmental assessment.

IX. Economic Impact

No statement of economic impact of the requested action has been requested at this time.

X. Certification

The undersigned certifies, that, to the best knowledge and belief of the undersigned, this petition includes all information and views on which the petition relies, and that it includes representative data and information known to the petitioner that are unfavorable to the petition.

Respectfully submitted,

 

____________________________

Steven A. Zecola

 

 

A Proposed Amendment to the 21st Century Cures Act

December 7, 2015 by Steven A. Zecola

  1. Introduction

Most people would agree that the number of cures for debilitating and costly illnesses such as Alzheimer’s disease, Parkinson’s disease and cancer have been too few and far between.

To address this issue, the U.S. House of Representatives recently passed the 21st Century Cures Act, which now resides in the U.S. Senate for action.  The main thrusts of the Act are to increase government funding for research and to improve several regulatory processes.

Unfortunately, the Act does not address the root cause of the dearth of cures; namely, the inhospitable investment climate for research and development (“R&D”) culminating in the “Valley of Death” for most health-related discoveries.

  1. Overview of the 21st Century Cures Act

The 21st Century Cures Act mandates a 3% real increase in the NIH budget per year for three years after enactment. It also provides an additional $1.86 billion a year in the form of an “innovation” fund that would primarily support young scientists and precision medicine.

The bill also provides for changes to the current approval processes including provisions for making data from NIH-funded clinical trials more easily available to researchers, facilitating collaborative research, speeding up the review of new vaccines by the Advisory Committee on Immunization Practices, requiring a strategic plan every five years to identify research opportunities and strategic focus areas, reducing administrative burdens on researchers, and limiting the term of office of directors of centers and institutes to five years (with reappointment by the NIH director possible). The bill also requires the directors of each institute to “establish programs to conduct or support research projects that pursue innovative approaches to major contemporary challenges in biomedical research that involve inherent high risk, but have the potential to lead to breakthroughs” and “set aside a specific percentage of funding, to be determined by the Director of NIH for each national research institute, for such projects.”

III. Critique of the Act

While the provisions of the 21st Century Cures Act are admirable, the Act does not address the underlying reason for the dearth of cures.  That is, the regulatory process adds excessive and unpredictable risk, cost, and delays to research and development that result in a “Valley of Death” where most scientific discoveries remain unfunded.

An approach to overcome this obstacle is summarized here and explained in more detail in a position paper posted at www.thevalleyofdeath.info .  In a nutshell, Congress needs to create an environment that provides for increased incentive for private capital formation to fund R&D without compromising consumer safety.

  1. Summary of Proposed Amendment to Address the Valley of Death in Research and Development

The following five provisions summarize the approach to improve private capital formation for research and development in health-related initiatives.

To ease any concerns between the balance of benefits and public safety with this program, the following recommendations could be rolled out in one or two areas such as Alzheimer’s disease, Parkinson’s disease and/or metastatic cancer where patients have more suffering and less hope for a cure.

The proposed approach is as follows:

1) Congress would limit the FDA’s role in preclinical research to surveillance.

2) Each pre-approved, qualified professional research organization filing a Phase 1 drug application would receive a provisional license from the FDA within 60 days from the time it provided the details of its trial and put a corresponding deposit into an escrow account.

Likewise, applications for Phase 2 and Phase 3 trials would also be subject to a 60 day review cycle and would require additional funds to be deposited into an escrow account, the amount of which would be subject to the size of the trials. A sample deposit schedule follows:

Phase 1 – $250,000 per trial participant

Phase 2-  $100,000 per trial participant

Phase 3 –   $50,000 per trial participant

The above schedule would produce escrowed deposits as follows:

 Number of Participants   Incremental Deposit Cumulative Deposit
Phase 1 20 – 40 $5M – $10M $5M – $10M
Phase 2 100 – 200 $10M – $20M $15M -$30M
Phase 3 1000 – 3000 $50M – $150M $65M – $180M

The FDA would have the authority to reduce the above deposits for special considerations.

3) An industry organization would be required to provide regular reports to the FDA for purposes of oversight (along with the reports provided by individual research organizations with the results of each phase of its trial). This industry organization would have the authority and responsibility to audit individual trial results and to maintain a secure whistle blower system.  A reward would be paid to whistle blowers whose efforts led to the successful prosecution of fraud by a licensee.

4) The FDA would have authority to seek injunctions from the U.S. Court of Appeals to stop any new drug, procedure or device that it believed was unfit for human application.  If a company were found to be in violation of the FDA’s safety guidelines, the company would lose its license and forfeit its escrowed funds.

5) Research organizations would be required to maintain and submit relevant health statistics on patients for one year from commercial launch.  Sixty days after such filings, the FDA would issue a commercial license and the escrowed funds would be returned to the licensee if a Court had not granted an injunction.

Likewise, if the research organization voluntarily abandoned its program during development, the deposit would also be refunded.

Such an approach would place the risk, pace and costs of both pre-clinical research and clinical trials principally under the control of qualified research organizations.  The effect would be greater funding opportunities for the private sector to pursue promising research opportunities.

In addition, the Amendment would strengthen the FDA’s surveillance and enforcement powers for purposes of protecting consumer safety, and put the proper incentives and penalties in place to forestall the introduction of unsafe products to the public.

  1. Conclusion

 

While the 21st Century Cures Act recognizes and addresses a significant issue in the health and welfare of our country, it does not solve the underlying problem causing the lack of significant health-related cures.

 

Congress could jumpstart private funding for research and development of promising discoveries by adopting the above recommendations in an Amendment to the 21st Century Cures Act.

 

To minimize concerns for public safety, the approach recommended here could be achieved with an Amendment that would apply only to specific research areas such as Alzheimer’s disease, Parkinson’s disease and/or metastatic cancer where suffering is the greatest and hope is fleeting.

 

Out of an even further abundance of caution, Congress could implement this Amendment on an optional basis, thereby letting research organizations choose between this approach and the more traditional approach outlined by the Act and the FDA.

 

#   #   #

 

A New Approach for Drug Approvals in the Age of “Big Data”

 

November 3, 2015 by Steven A. Zecola

I. Introduction and Summary

The amount of health-related information available to researchers is expanding exponentially as a result of the technical advancements in the world of “Big Data”. To most people, this signifies a quicker path to cures of debilitating diseases and/or to better care of people on a personalized basis.

But that is not how the current system works. Under its legislative charter, the Food and Drug Administration (“FDA”) stands between every promising cure and the implementation of that cure.  Its approval process imposes an average of 12 years of development and a cost of over $1 billion per approved drug.  As a result, this system creates a valley of death that most new healthcare solutions fail to cross. For example, the FDA approves only about 25 new drugs per year.

In contrast, the Chemical Abstract Service (CAS) adds 15,000 substances – per day – to its registry; and that number is growing.  For example, CAS recently registered a novel therapeutic designed to treat acute myeloid leukemia as its one hundred millionth entry.

While Congress put the FDA’s regulatory structure into motion decades ago, it has done very little to curb the excessive delays and costs or address the challenges of the valley of death.

Rather than a tweak here and a tweak there, the entire system needs a major overhaul.

In particular, to significantly improve healthcare for both healthy and unhealthy people, Congress should leverage the capabilities and resources of the private sector for quicker implementation and more efficient safety procedures.

As described herein, Congress should require the FDA to provide provisional licenses after a 60 day review period to all qualified applicants who put a $5-10 million bond into an escrow account for a Phase 1 trial. These escrowed funds would escalate in size for Phase 2 and Phase 3 trials, depending upon the magnitude of the trials.

Each licensee would provide reports to the FDA for each phase of its research.  The FDA could seek injunctions for any trials that it believed would harm public safety. If granted by the court, the research organization would lose its provisional license and the escrowed funds.

If the FDA and the courts did not block new drugs and treatments from becoming effective, the escrowed funds would be returned to the developer one year after commercial launch and a commercial license for such drug or treatment would be issued by the FDA at that time.

Such an approach would hasten and improve the advancement of effective cures by dramatically reducing the risk, time and cost of drug development, while minimizing the risk of adverse consequences from research and development.

II. The History of FDA Regulation

The original 1906 Food and Drugs Act prohibited the contamination or misbranding of pharmaceuticals, but did not require premarket approval of drugs. As long as drugs were properly labeled and conformed to the applicable guidelines, there was no federal statute to prevent their commercialization.

This legislation stood until 1938 when President Roosevelt signed the Food, Drug, and Cosmetic Act, which revamped oversight of food and drugs and included consumer protection over medical devices and cosmetics.

The provisions of the new law required manufacturers to submit to the FDA evidence of a drug’s safety before it could go on the market, and the agency had two months to approve, reject, or request additional data from the firm. This mandate for premarket evidence of a drug’s safety represented the birth of the new drug application, or NDA.

In 1962 Congress amended the drug provisions of the law to require, among other items, that manufacturers establish not only the safety but also the effectiveness of the drug through adequate and well-controlled clinical trials prior to marketing. This change was responsible for the expansion of the drug application into a massive document of perhaps hundreds of volumes.

Since that time, there have been several legislative adjustments to the process.  For example, in 1988, Congress adopted The Prescription Drug Marketing Act and modified it in 1992 to ban the diversion of prescription drugs from legitimate commercial channels. The law also requires drug wholesalers to be licensed by the states; restricts re-importation from other countries; and bans sale, trade or purchase of drug samples, and counterfeiting of redeemable drug coupons.

In 1997, the Food and Drug Administration Modernization Act reauthorized the Prescription Drug Act of 1992. Its provisions include measures to review medical devices and to regulate advertising of unapproved uses of approved drugs and devices.

III. The Success and Tribulations of the Current Drug Approval System

The FDA has broad responsibilities. For example, it regulates more than $1 trillion worth of consumer goods, about 25% of consumer expenditures in the United States. This includes $466 billion in food sales, $275 billion in drugs, $60 billion in cosmetics and $18 billion in vitamin supplements.

One method of measuring the success of the current system is the number of drug approvals per year.

US FDA

As the chart shows, the number of new drug approvals per year is shockingly low.

Moreover, in contrast to what it has done (as shown in the chart above), the FDA doesn’t report what it hasn’t done.  For example, earlier this year a CBS 60 Minutes report on the use of polio virus to kill brain cancer disclosed that the FDA had delayed this promising treatment for almost a decade with pre-clinical study requirements.

The cost, delays and risk of the regulatory scheme are substantial. The result is a hostile investment climate that creates a valley of death for new healthcare initiatives.

IV. The Pace of Technological Advancement in Healthcare

Society, in general, is experiencing an explosion of information, its storage and its processing; commonly referred to collectively as “Big Data”.

For example, more information is produced every two days than was produced from the beginning of time to 2003. And 90% of the available data in the world was created in the last two years. By 2020, the amount of digital information is projected to have increased from 3 zettabytes to 40 zettabytes.

In healthcare, Big Data fundamentally changes the approach to experimental design. Today, researchers can afford to collect virtually unlimited amounts of data and search for significant patterns in the data.

For example, Flatiron Health has developed a service called “OncologyCloud”, based on the idea that 96% of potentially available data on patients with cancer is not yet analyzed. It aims to take this data gathered during diagnosis and treatment, and make it available to clinicians to further their studies.

In genetics, what took 10 years to uncover about the human genome would now take one week.  And the analysis of genomes generates even more data.

The ability and pace for scientists to address today’s many illnesses is exploding.   And with the use of personal genetic information, the treatments can become highly individualized and much more effective.

But the potential benefits from Big Data are not confined to curing only the sick.  Information is becoming available that will enable doctors to alter a patient’s health trajectory.    For example, a mutation in the BRCA1 gene is destined to produce breast cancer in 85% of all carriers.  Thankfully, an effective vaccine is within reach given the ongoing research into Parp Inhibitors.

One way to see the explosion of potential opportunities is in the number of new chemical substances. The following chart shows the growth rate in new substances registered by the Chemical Abstract Service (CAS) each year.

CAS Registry

While the technology is advancing at breakneck speed and producing many potential healthcare solutions, the current drug approval process is extraordinarily slow and expensive and most solutions don’t make it across the valley of death.

V. The Cost and Benefits of FDA Regulation

The greatest cost to society from the current drug approval process cannot be seen.  That is, viable healthcare solutions are being delayed or worse yet, are not being developed at all because of the expense and risk of approval.

For example, in addition to gaining a better understanding of the process of metastasis, scientists are now uncovering new compounds and potential avenues of treatment.  However, research for many of these compounds has not occurred in humans.  The principal reason for this vacuum is that the existing clinical trial design ensures that these compounds will fail.  In particular, the compounds are not designed to meet the FDA’s Phase 2 requirement of shrinking existing tumors.

Nevertheless, in rejecting my Petition to put increased focus and new procedures into place for trials of metastatic cancer, the FDA said it “does not believe that its current structure lacks ‘sufficient organizational focus’ on metastatic disease, is inefficient or otherwise impedes the conduct of clinical trials or products intended to either treat or retard the  development of metastatic cancer.”  Yet the system has failed miserably in bringing viable solutions to the market – and the public is paying the price from delay.

We know that increased focus and new treatments will have important benefits to society.  For example, as new anti-HIV drugs became available, the annual death rate from HIV declined by 63%.   Likewise, new heart drugs correlated with a 45% drop in coronary-artery disease.

There are many targets ripe for additional focus. The following table provides examples of chronic diseases in the United States.

Disease Population Affected Impact
Asthma 26 million 11 million missed school days; 2 million emergency visits
Alzheimer’s 5 million Debilitating illness leading to need for increasing care and to early death
Breast cancer 3 million 50,000 deaths per year
Diabetes 26 million 37 million medical visits per year
Epilepsy 3 million Seizures leading to lost productivity
Heart disease 27 million 12 million annual medical visits; 2 million annual outpatient department visits; 600,000 annual deaths

 

Taken together, chronic diseases cause 7 of every 10 deaths in America. Moreover, about 25% of people with chronic diseases have some type of activity limitation such as needing help with dressing or bathing or being restricted from work or attending school.

By any measure, chronic diseases take a heavy toll on the nation’s wealth and health. For example, heart disease and stroke are estimated to cost about $432 billion per year. Diabetes costs are estimated to be about $174 billion per year.  And Alzheimer’s is estimated to add about $148 billion per year.  In total, well over 50% of the $3 trillion spent on health care each year is attributable to chronic diseases.

Small improvements in bringing effective treatments to market can have a big impact on society in several different ways.

First, the cost of treatment will decrease. For example, the annual costs for diabetes care have been shown to drop almost 50% for patients who take their diabetes medicines properly.

Second, quicker availability of effective treatments can have a big impact by bringing down costs earlier. For example, we know that the length of time for the FDA approvals began increasing after the 1962 Amendments; from about 1 year to 3 years by the end of the decade and then up to 10 years in the 1970’s. Viewed in this light, the lag introduced by the current FDA drug approval process would appear to be at least 5 years, especially when including pre-clinical reviews.

Third, development costs would be lower under a revised system.  For example, the cost of research and development per approved drug has increased from $100m in 1975 to $300 million in 1987 to over $1 billion more recently.  Total R&D spending in the industry exceeded $800 billion from 1997 to 2011 even with high regulatory involvement and risk.  An improved regulatory system could reduce the average cost per approved drug by up to 50% without an undue risk to public safety, as described in Section VI.

Cumulatively, the implication of these numbers is staggering. For example, if effective new treatments came to market 5 years earlier under a revised regulatory regime and addressed 10% of all chronic diseases, this would save society $750 billion over time.  Similarly, a more streamlined process with industry participation in safety management would save up to $50 billion per year in unnecessary regulatory red tape.

On the other side of the coin, the FDA regulation produces benefits to society by keeping unsafe drugs out of trials and away from the broader public marketplace.  Undoubtedly, there are instances in which this would happen without any oversight. A classic example is the “Elixir Sulfanilamide tragedy” which led to the legislation in 1938. In 1937, a Massengill, a Tennessee drug company, began to market a liquid drug called Elixir Sulfanilamide.  The solvent in this drug was highly toxic variant of antifreeze; as a result, over 100 people died from taking this drug.

Similarly, the 1962 Drug Amendments legislation was passed in response to a therapeutic crisis – in this instance, the discovery that the use of thalidomide (a sedative that was marketed to combat the symptoms associated with morning sickness) by pregnant women caused birth deformities in thousands of babies in Europe.

With complete deregulation, there may be such adverse impacts to thousands of people per year.  If 1000 such instances were to occur per year and we put a punitive value of $1 million on each instance, the benefit of effective regulation in mitigating such circumstances would equate to $1 billion per year.  But even in this contrived example, these benefits would equate to less than one half of one percent (0.5%) of the hidden cost that regulation perpetrates from delays of new healthcare solutions.

More to the point, there is a way to minimize the risk to safety while maximizing the possibility of expedited healthcare solutions, as described in the following section.

VI. Recommendation for an Alternative Approach to the Regulation of New Drug Discovery

The existing legislation for drug discovery puts the FDA smack in the middle of all health-related research.

The FDA monitors and approves new solutions in the lab and from preclinical animal studies through 3 or 4 phases of clinical trials.  Oftentimes, trial design is set by the FDA. Hundreds of thousands of pages of information are provided to, reviewed by, and approved by the FDA before any progress can be made. Given the hostile investment climate created by this system, very few healthcare solutions can cross the valley of death.

However, by adjusting the responsibility for public safety and effectiveness to include industry participation, the number of new, effective solutions would increase dramatically given the improved investment climate. The issue would then become how to minimize undue harm to the public from this adjustment.

In a nutshell, an effective way to expedite scientific progress while curbing the risk of harm to the public is as follows:

1) Congress should limit the FDA’s role in preclinical research to surveillance.  That is, all Phase 1 clinical trials by qualified research organizations should be presumed to be valid by the FDA.

2) Each pre-approved, qualified professional organization filing a Phase 1 drug application would receive a provisional license from the FDA within 60 days from the time it provided the details of its trial and put a $5-10 million deposit into an escrow account.

3) Likewise, applications for Phase 2 and Phase 3 trials would be subject to a 60 day review cycle and would require additional funds to be deposited into an escrow account, the amount of which would be subject to the magnitude of the trials.

4) The industry would be required to take over and expand the function of the website Clinicaltrials.gov to develop a self-reporting and surveillance mechanism.  The resulting industry organization would provide regular reports to the FDA for purposes of oversight (along with the reports provided by individual companies with the results of each phase of its trial). The industry organization would have the authority to audit individual trial results and to maintain a secure whistle blower system.  A $1 million reward would be paid to whistle blowers whose efforts led to the successful prosecution of fraud by a licensee.

5) The FDA would have authority to seek injunctions from the U.S. Court of Appeals to stop any new drug or procedure that it believed was unfit for human application.  If a company were found to be in violation of the FDA’s safety guidelines, the company would lose its license and forfeit its escrowed funds.

6) Drug companies would be required to maintain and submit relevant health statistics on patients for one year from commercial launch.  Sixty days after such filings, the FDA would issue a commercial license and the escrowed funds would be returned to the licensee if a Court had not granted an injunction.

7) Out of an abundance of caution, Congress could phase in such an approach.  For example, it could apply such an approach in one or two research areas such as Alzheimer’s or Parkinson’s disease and/or metastatic cancer.

8) Under a phased approach, Congress would review the costs and benefits of the new approach triennially. The current drug approval process would sunset in 10 years unless Congress found the new approach to be flawed.

This proposal does not represent a radical deregulatory approach.  In fact, it is more stringent than the current practice of doctors prescribing “off-label” uses (that is, uses not approved by the FDA) of drugs approved for other conditions.  For example, doctors routinely prescribe Amoxicillin for stomach ulcers, although this drug has never been through any trials for this application.  Yet there is not any failure of the market to digest and utilize the latest information for off-label drugs to the benefit of consumers with very little safety risk.

Likewise, under the system proposed herein, scientists and doctors, working through professional organizations, would make determinations on the best available treatment for patients.  The FDA’s role would be limited to oversight and enforcement.  As a result, the investment climate would improve considerably and any new healthcare solutions would be able to cross the valley of death.

VII. Conclusion

Under its legislative charter, the FDA‘s actions not only can be quite limiting on research organizations, but they can also be hard to predict.

For example, with respect to personal genetic service, the FDA asserted its jurisdiction over the 23andMe.com offering by finding it to be a “device” that was “intended for use in the diagnosis of disease or other conditions or in the cure, mitigation, treatment, or prevention of disease”. It then found 23andMe to be in violation of the Federal Food, Drug and Cosmetic Act by marketing its product without prior approval from the FDA. The agency noted that 23andMe provided individual reports on 254 diseases and conditions and that the FDA expected 23andMe to get prior approvals for each of these reports. As the 23andMe CEO and co-founder, Anne Wojcicki, explained in response, the FDA system would require it to get approvals for over one million tests. Of course, that would be practically impossible for either party to accommodate.  As a result, it took two years for 23andme.com to get FDA approval for a subset of  its reports.

On the other side of the coin, the FDA can arbitrarily dismiss concerns for public safety (arguably to protect the status quo). For example, in denying my Petition to halt the use of ACT chemotherapy for breast cancer patients with a BRCA1 mutation, the FDA said, in part, “There are side effects with all chemotherapeutic agents (not just ACT)”.

Given the intensive FDA involvement, the delays, costs and risks of the current drug approval process are too great for most healthcare solutions to get  funding to cross through the valley of death.

Viewed in this light, the greatest beneficiaries of the current drug approval process are the large pharmaceutical companies who are protected from competitive entry.  Yet under the approach proposed herein, these pharmaceutical will be able to compete for new cures on an equal footing.

More importantly, by shifting the responsibility for public safety and effectiveness to licensed research organizations and putting strong oversight by the FDA into place with punitive remedies for jeopardizing public safety, the advancement of safe and effective new cures will accelerate without undue risk of harm.  In quantitative terms, the gains to society will be more than one hundred times greater than the cost of the increased risk to public safety.

Likewise, the pharmaceutical companies will play a larger role in the process and stand to benefit from the faster implementation of viable healthcare solutions.

The impetus for change to the drug approval process may not be publicly visible, but it would be a godsend to the public. In actuality, the FDA has done a good job given its expansive charter.  However, the FDA’s legislative charter is the kiss of death for millions of people who will never experience the benefits from the healthcare solutions emanating from the world of “Big Data”. It is time for Congress to recognize this national tragedy and to do something about it.

 

Zecola Issues a Rebuttal to the FDA’s Denial of the Petition to Withdraw Support for ACT Chemotherapy for BRCA1 Patients

On July 9, 2014, the FDA denied the Citizen Petition filed by Steven Zecola for it to withdraw support of ACT chemotherapy for BRCA1 breast cancer patients. The core of the FDA’s rationale is that: “Available evidence indicates that ACT drugs approved for the treatment of breast cancer are effective in BRCA1 TNBC patients”.   See Denial at page 9. For support of this finding, the FDA references Lee L.J., B Alexander, et al., 2011, “Clinical outcome of triple negative breast cancer in BRCA1 mutation carriers and noncarriers”, Cancer, 3093-3100.

However, the FDA fails to recognize that this study finds: “the 10-year survival rates for women who received adjuvant chemotherapy were 71% for carriers [and]….Among women who did not receive chemotherapy, the 10-year survival rates were 75% for carriers…”  That is, the survival rates were better for BRCA1 carriers who did not take chemotherapy.

The FDA makes several other critical omissions.  For example, it says: “There is no standard targeted treatment for TNBC (with or without a BRCA1 mutation)”.  However, the above study notes that “the majority of chemotherapy regimens contained an anthracycline backbone (91%), most commonly doxorubicin and cyclophosphamide (AC), doxorubicin, cyclophosphamide, 5- fluoruracil (CAF) or doxorubicin, cyclophosphamide followed by paclitaxel (AC+T).   Additionally, the National Comprehensive Cancer Network recommends ACT for TNBC.

The FDA also fails to recognize a critical finding of the above report, namely, “In a recent report of 102 women with BRCA-1 related breast cancer, the pathologic complete response (CR) rate for 12 patients treated with neo-adjuvant cisplatin on a clinical study was 83%, compared to 22% for the 51 BRCA1 mutation carriers who received AC in a retrospective comparison.”

The FDA also dismisses the disproportional side effects of ACT chemotherapy by saying: “There are side effects with all chemotherapeutic agents (not just ACT).”  However, as I pointed out in the Petition: “These chemicals also cause hair loss, nausea, and pain among many other unpleasant side effects, including increased emotional stress”.  Platinum-based agents do not have nearly as many or as severe side effects.  The impact of side effects should be included in the decision to authorize drugs as well as in comparing one drug versus another.

The FDA says that the Petition did “not presented any evidence suggesting that side effects are more deleterious in BRCA1 patients being treated with ACT drugs than in other patients”.  However, that is the wrong standard and wrong comparison.  The relevant treatment choices for BRCA1 breast cancer patients after surgery are: ACT, Carboplatin/Parp inhibitors (currently in clinical trials), or no chemotherapy.    ACT provides the poorest outcome of these options and the worst side effects.  These are the proper measures that the FDA should be considering in comparing treatment options.

Because of the FDA’s shortsightedness, 15,000 women with BRCA1-related breast cancer will be prescribed a regimen of ACT chemotherapy each year for the next several years until carboplatin and Parp Inhibitors overcome the obstacles of the regulatory process.

It is clear why the current FDA process benefits the incumbent pharmaceutical companies.  It is not clear how the process — which is designed to protect the status quo — benefits the public.

The conflict between regulation and technological advancement will increase as the FDA’s regulatory strait-jacket is applied to the growing number of solutions derived from the application of “big data” correlations to individual genetic information to derive new solutions.

The solution requires political action, but it will not be coming from the FDA.