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 “precisionFDA” program 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.
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.
ii) Each 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.
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.
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.
Steven A. Zecola