August 2, 2016

Division of Dockets Management (HFA-305)

Food and Drug Administration

5630 Fishers Lane, Rm. 1061

Rockville, MD 20852

Comments of members of the Patient, Consumer, and Public Health Coalition

on

Labeling for Biosimilar Products; Draft Guidance

[FDA-2016-D-0643]

Members of the Patient, Consumer, and Public Health Coalition support the Food and Drug Administration’s (FDA) draft guidance on “Labeling for Biosimilar Products.”  The draft guidance will protect patients and consumers by requiring biosimilar companies to update their labels when safety issues arise.

Background

The Biologics Price Competition and Innovation Act of 2009, signed into law as part of the Affordable Care Act, created an abbreviated pathway to license biosimilar products.[i] A product is a biosimilar if it has no clinically meaningful differences compared to the reference product in terms of “safety, purity, and potency.”¹ Because there is no meaningful difference, we agree with the FDA that biosimilars labeling should include a description of the clinical data that supported safety and efficacy of the reference product.  We agree with FDA that the biosimilar prescribing information (package insert) relies mainly on the safety and effectiveness information from the labeling for the reference product.[ii] 

Specific Recommendations on Content of Biosimilar Product Labeling

FDA also notes that biosimilar products’ labels may differ from the reference product labeling (have “appropriate product-specific modifications”) in order to conform to the Physician Labeling Rule (PLR) and the Pregnancy and Lactation Labeling Rule (PLLR), and other safety issues.  We agree since this will add to the safer use of biosimilars.  Also, according to a recent survey of European physicians, they “prefer more product-specific information in the biosimilar label.”[iii]

 Revising Biosimilar Product Labeling

We strongly agree with the FDA that “all holders of marketing applications for biological products have an ongoing obligation to ensure their labeling is accurate and up to date” (emphasis added).¹  We see no reason why this should not include PLR and PLLR information for the reference product. To ensure that the product is used safely, both the reference product and the biosimilar product application holders must be able to update their labeling.

 Conclusions

We strongly support the “Labeling for Biosimilar Products” draft guidance.  It will protect patients and consumers by ensuring the important labeling safety information is updated for both biosimilars and the reference products.

American Medical Student Association

American Medical Women’s Association

Center for Medical Consumers

Connecticut Center for Patient Safety

MAME

MRSA Survivors Network

National Center for Health Research

National Physicians Alliance

National Women’s Health Network

Quinolone Vigilance Foundation

Washington Advocates for Patient Safety

WoodyMatters

 The Patient, Consumer, and Public Health Coalition can be reached through Paul Brown at (202) 223-4000 or at pb@center4research.org

[i] Federal Register (April 4, 2016). Food and Drug Administration draft guidance “Labeling for Biosimilar Products.”

[ii] Food and Drug Administration (April 1, 2016).  News & Events Form our perspective: Biosimilar product labeling.

http://www.fda.gov/Drugs/NewsEvents/ucm493240.htm?source=govdelivery&utm_medium=email&utm_source=govdelivery 2/3

[iii] Hallersten A, Fürst W, Mezzasalma R (June 2016). Physicians prefer greater detail in the biosimilar label (SmPC) – Results of a survey across seven European countries.  Regul Toxicol Pharmacol. 

http://www.ncbi.nlm.nih.gov/pubmed/27041395

July 25, 2016

Division of Dockets Management (HFA-305)

Food and Drug Administration

5630 Fishers Lane, Rm. 1061

Rockville, MD 20852.

Comments of members of the Patient, Consumer, and Public Health Coalition on

Proposed Rule To Ban Electrical Stimulation Devices Used To

Treat Self-Injurious or Aggressive Behavior

[Docket No. FDA-2016-N-1111]

Members of the Patient, Consumer, and Public Health Coalition strongly support the FDA’s proposed rule to ban electrical stimulation devices (ESDs)* used to treat self-injurious behavior (SIB) or aggressive behavior (AB). ESD treatments are ineffective and have serious side effects, and there are alternative, less stressful treatments available.

The goal of ESDs is to reduce self-injurious or aggressive behavior by punishing it with shocks.  However, the strategy of preventing violent behavior in any situation by using a painful punishment is rejected by most experts.  That is why the overwhelming majority of SIB and AB patients are not treated with ESDs.  Only one facility in the U.S. manufactures and uses ESDs, the Judge Rotenberg Educational Center, Inc. (JRC). Even if ESDs were a safe, effective, and humane treatment, those used by JRC as recently as 2012 had not been cleared by the FDA. FDA has sent warning letters to the Center at least three times stating that the devices are in violation of FDA regulations because they have been modified to increase the voltage they provide but a new application has not been filed with the FDA.[i]^, [ii]

Because of advances in human rights and behavioral therapy, nearly half of the States prohibit the use of ESDs.[iii] The United Nations has said use of ESDs, such as those used by the Rotenberg Center, constitutes a violation of the UN Convention Against Torture, and would not be legal if used even against convicted terrorists.[iv]^, [v]

Risks

ESDs have a long list of harms including “depression, PTSD, anxiety, fear, substitution of other negative behaviors, worsening of underlying symptoms, and learned helplessness, as well as the physical risks of pain, and skin burns.”³ The devices are associated with an increased risk of “suicidality, chronic stress, neuropathy, and injuries from falling.”³  They are associated with “nightmares, flashbacks of panic and rage, hypervigilance, insensitivity to fatigue or pain, changes in sleep patterns, loss of interest, difficulty concentrating, and withdrawal from usual activity.”³

We agree with the FDA that adverse events are likely to be under-reported because the children and adults subjected to ESD often have problems that make it difficult to persuasively communicate to anyone who would be likely to report adverse events to the FDA.   In addition, the individuals administering ESDs are unlikely to be taught or encouraged by their employer (who requires them to administer ESDs) to report adverse events resulting from ESD “treatment.”

Benefits

Although the scientific literature reports that ESD shocks can immediately interrupt SIB or AB, these studies have been criticized for “weak study design, failure to control for concomitant treatments, small size, lack of peer review, and conflicts of interest.”³  We agree with the FDA that “the evidence is inadequate to establish that ESDs improve individuals’ underlying conditions or…reduce or cease the target behavior to achieve durable long-term reduction of the target behavior.” The established risks are even more unacceptable given the lack of evidence of benefits.

Alternative treatments

There is clear research evidence that positive reinforcement is more effective and longer-lasting than negative reinforcement (punishment).  We agree with the FDA that positive-based behavioral approaches are effective at reducing self-injurious and aggressive behavior, providing greater benefits and less risk than ESDs.  We also agree with the FDA that “addressing the underlying causes of SIB and AB…rather than suppressing behaviors with shocks not only avoids the risks posed by ESDs, but can achieve durable, long-term benefits.”

Conclusions

ESDs are not established to be effective for most self-injurious or aggressive behaviors and represent a substantial and unreasonable risk of injury.  They are also inhumane. For the above reasons, we strongly support the ban on electrical stimulation devices.

American Medical Women’s Association

MAME

MRSA Survivors Network

National Center for Health Research

National Physicians Alliance

Washington Advocates for Patient Safety

WoodyMatters

The Patient, Consumer, and Public Health Coalition can be reached through Paul Brown at (202) 223-4000 or pb@center4research.org

*We are aware that ESDs are not used in electroconvulsive therapy (ECT or electroshock therapy) and that this proposed rule does not apply to ECT devices.

[i] Willingham E (April 22, 2016).  FDA Proposes Ban On Electric Shock Devices Used On Autistic Children. Forbes. http://www.forbes.com/sites/emilywillingham/2016/04/22/fda-seeks-to-ban-electric-shock-devices/#7e7c39e87ead

[ii] Food and Drug Administration (December 6, 2012).  Inspections, Compliance, Enforcement, and Criminal Investigations: Warning Letter CMS#367480, the Judge Rotenberg Educational Center. http://www.fda.gov/ICECI/EnforcementActions/WarningLetters/2012/ucm331291.htm

[iii] Federal Register (April 25, 2016). Food and Drug Administration: Banned Devices; Proposal To Ban Electrical Stimulation Devices Used To Treat Self-Injurious or Aggressive Behavior; Proposed Rule. [Docket No. FDA-2016-N-1111] https://www.federalregister.gov/articles/2016/04/25/2016-09433/banned-devices-proposal-to-ban-electrical-stimulation-devices-used-to-treat-self-injurious-or

[iv] Ahem, L (October 2, 2010). Disabled children at Mass. School are tortured, not treated. The Washington Post. http://www.washingtonpost.com/wp-dyn/content/article/2010/09/17/AR2010091705376.html

[v] Burkholder A (August 5, 2014). Controversy over shocking people with autism, behavioral disorders. CBS News. http://www.cbsnews.com/news/controversy-over-shocking-people-with-autism-behavioral-disorders/

July 18, 2016

Food and Drug Administration

Division of Dockets Management (HFA-305)

5630 Fishers Lane, Rm. 1061

Rockville, MD 20852

Comments of members of the Patient, Consumer, and Public Health Coalition

on the draft guidance

Use of Electronic Health Record Data in Clinical Investigations

[Docket No. FDA-2016-D-1224]

A major goal of the draft guidance is to “facilitate the use of EHR data in clinical investigations.”¹  Although EHRs are not under the direct control of the FDA (the systems belong to healthcare organizations and institutions that use them), the Agency does need to develop a clear process for accepting EHR data for use in clinical investigations.  The draft guidance is a step in the right direction but needs to better address key issues.

The draft guidance addresses how the FDA will ensure the EHR data’s validity, reliability, and integrity, and how the agency will verify the integrity of the EHR data during on-site inspections and audits of the organizations that control the data.

On-site inspections

We agree with the draft guidance that clinical investigators must retain all paper and electronic source documents for as long as required by regulations, and EHR data must meet FDA’s inspection, record keeping and record retention requirements.  And, importantly, study monitors must have “suitable access to all relevant subject information pertaining to a clinical investigation.” ²

However, we are concerned that the draft guidance does not mention how often FDA will do on-site inspections.  If FDA does not establish a schedule of on-site inspections, they may never be done and this could lead to poor quality data.

Quality and integrity

The draft guidance states that “when EHRs are used as a source of data in clinical investigations, sponsors should ensure that the data are ‘attributable, legible, contemporaneous, original and accurate (ALCOA).’”  If the data does not meet all five of these attributes, will the data be rejected by the FDA?

An inherent problem with using EHRs for clinical investigations is that EHRs are currently designed to assist in delivering health care — not to generate medical evidence.  A July 2016 Article in JAMA Internal Medicine notes that “practices like blinding, randomization, or standardized-event recording are more difficult to implement in systems that are oriented toward care.  Health care systems represent inefficient environments to which to learn about differential effects of novel drugs.”³ The draft guidance notes that the use of EHRs for clinical investigations may require additional “considerations, planning, and management” but it does not go into detail on how to accomplish this.

The draft guidance recommends, but does not require, the use of certified EHR technology.  The U.S. Department of Health and Human Services’ Office of the National Coordinator for Health Information Technology (ONC) has a voluntary certification program for health IT.  EHR technology certified by ONC’S Program meets privacy and security protection requirements.

The draft guidance allows EHRs not certified by ONC to be used for clinical investigations as long as they include adequate controls such as limiting access to the electronic systems, identifying the authors of records, providing audit trails, ensuring records are retained for FDA inspections, and assuring patient privacy rights.  Although the adequate controls address key issues, there would be more consistency in investigations, if all EHRs for clinical investigations were required to use certified EHR technology.

In using EHRs for clinical investigations, the draft guidance recommends that extracted data is checked for consistency and completeness.  It also recommends that corrections be made when errors are found “to properly align the source data with the extracted data.”  We are concerned that unless FDA spot checks the data, errors will not be corrected.

The draft guidance notes that software updates could “affect the reliability and integrity of EHR data entering the sponsor’s electronic system.”  This is a major concern.  A recent review of FDA data by the National Center for Health Research found that over the last 5 years, more than 600 different software devices totaling over 1.4 million units were recalled for moderate or high risk patient safety issues.  For example, oncology electronic medical record systems were recalled because they erroneously switched patient data and failed to warn physicians about dangerous drug reactions.

Interoperability & audit trails

The draft guidance encourages the use of interoperable systems in order to “reduce errors in data transcription and provide data that is more accurate.”  We agree that interoperability will reduce transcription errors but if the data was incorrect to begin with, it will not provide more accurate data.

The draft guidance states that adequate methods of audit trails are needed to monitor, track and document all changes made to information in the EHR regarding the clinical investigation. However, the draft guidance fails to define the phrase “adequate methods.”

One of the major risks associated with EHRs are data breaches.  Data breaches could negatively affect a subject’s employment or ability to get insurance.  The draft guidance states, “Sponsors should consider whether there are any reasonably foreseeable risks with the use of EHRs…that must be described to the subject in the informed consent.”  We recommend that the risk of data breaches be communicated to subjects at least twice—once in writing and once again verbally.

Conclusions

EHRs can provide investigators “access to real-time and longitudinal health care data”¹and can provide post-trial follow-up information on safety and efficacy of medical products.  However, we think this draft guidance still needs work.  It does not address how inaccuracies in the data will be corrected, how often FDA will do on-site inspections, and ways to mitigate the risks of data breaches.

American Medical Women’s Association

MRSA Survivors Network

National Center for Health Research

Our Bodies Ourselves

Quinolone Vigilance Foundation

Washington Advocates for Patient Safety

The Patient, Consumer, and Public Health Coalition can be reached through Paul Brown at (202) 223-4000 or pb@center4research.org

May 24, 2016

The Honorable #{Fname} #{Lname}

United States Senate

Washington, DC 20510

Dear Senator #{Lname},

A recent STAT-Harvard poll shows that a majority of Americans oppose changing federal regulations to speed the development and approval of new medical products. They are concerned that speeding approvals would lower safety and effectiveness standards for medical products.⁴ As members of the Patient, Consumer, and Public Health Coalition, we share those concerns.  We also write to emphasize that any effort to develop safe and effective medical products should include mandatory new funding for the National Institutes of Health (NIH) and the Food and Drug Administration (FDA).

The House’s 21st Century Cures Act and its Senate companion legislation should focus more on ensuring that medical products are safe and effective and less on speeding medical products to the market. We appreciate that the Senate bills were less dangerous for patients than the House legislation. But, we opposed 6 of the 19 bills that the Senate passed out of the HELP Committee because they were not beneficial to patients.

When these bills (which we’ve listed below) reach the Senate floor, we strongly urge you to oppose them because they weaken FDA’s safety and effectiveness standards.

 Current and former FDA Commissioners have expressed their concerns as well. Current FDA Commissioner, Robert Califf recently said, “This legislation, if not carefully crafted, could pose significant risks for FDA and American patients…Innovative therapies are not helpful to patients if they don’t work, or worse, cause harm.” ⁵ Former FDA Commissioner David Kessler, who in the 1990s led the FDA under presidents from both parties, said, “It’s time to uncouple the promise of research funding from the requirement that FDA standards be lowered.”⁶

The underlying premise of the House and Senate bills seems to be that the FDA needs to speed up its approval process. This premise is based on the erroneous claim that other countries approve medical products more quickly. Nearly two-thirds of the novel drugs approved in 2015 (29 of 45, 64%) were approved in the United States before being approved in any other country.⁷ In fact, a Forbes article expressed concern that the pendulum has swung too far and that “the FDA is basically providing a rubber stamp” for drug approvals and that drug approvals are at an all-time high.⁸ Similarly, research indicates that “it takes the same amount of time or less for patients to gain access to innovative, high-risk medical devices” in the U.S. as compared to Germany, France, Italy, and Britain.⁹ Approximately 99% of all regulated medical devices are cleared by the FDA through the speedy and less-than-rigorous 510(k) process, and the FDA reviews 90% of those applications within 90 days.¹⁰ With the emphasis on speed over safety it is not surprising that millions of Americans have been harmed needlessly from defective medical devices such as surgical mesh, metal-on-metal hips, power morcellators, duodenal scopes, birth control devices (Essure), and inaccurate medical device software. It is clear that we need stronger device safety regulations and better postmarket surveillance. When there are problems with medical devices in the real world, patients need to be notified as soon as possible.

Members of our coalition are particularly concerned about the following bills:

MEDTECH Act (S. 1101)

The MEDTECH Act deregulates Electronic Health Records (EHRs) and other electronic health technology. This prevents the FDA from collecting adverse event data or recalling defective software, even when the devices have life-threatening flaws.  The National Center for Health Research studied FDA-reported recalls of medical software, identifying more than 600 software devices and 1.4 million units recalled for moderate or high risk patient safety issues.  They found that if medical software is removed from FDA regulatory oversight, millions of patients would be at risk from defective software. For example, oncology electronic medical record systems were recalled in the past because they calculated and recorded incorrect drug dosages. Clinical decision support systems used during surgery were recalled because they erroneously switched patient data and failed to warn physicians about dangerous drug reactions.

Advancing Breakthrough Devices for Patients Act (S. 1077)

This bill would set a low bar for medical devices to qualify for breakthrough status, and encourage shorter or smaller clinical trials, which would make it difficult if not impossible to include subpopulations (women, seniors, racial and ethnic minorities) in the analysis of the trials. The bill would also push FDA to rely on post-market studies rather than ensuring safety or effectiveness before hospitals and patients pay for the devices. A 2015 GAO report found that most required post-market device studies are never completed. In other words, if this bill passes, there would be no conclusive evidence pre-market or post-market.

The Advancing Hope Act (S. 1878)

Priority review vouchers allow FDA priority reviews to go to the highest bidder rather than allowing the FDA to prioritize matters of the most public health importance.  The bill’s priority review vouchers would be applied to drugs that are already in development rather than spurring new drugs because of the long drug development cycle.

The Medical Countermeasure Innovation Act (S. 2055)

This bill establishes a new priority review voucher program for medical countermeasures (e.g. antidotes to anthrax and other bioweapons). As with existing priority review voucher programs, it does not necessarily reward innovation and prevents FDA from prioritizing matters of greatest public health importance.

The Combination Product Regulatory Fairness Act (S. 1767)

This bill would broaden the ability of combination products to be classified as devices.  This would inappropriately allow products that should be classified as drugs to go through the FDA’s less rigorous device clearance/approval process.

Patient Focused Impact Assessment Act (S. 1597)

The Patient Focused Impact Assessment Act adds a new layer of bureaucracy to the FDA, does not provide safeguards to ensure that patient perspectives will be free of industry influence, and may provide a mechanism for industry to promote drugs directly to consumers for off-label uses.

REGROW Act (S. 2689)

The REGROW Act is the latest effort to lower research standards and deregulate new treatments. Although this bill was not part of the HELP Committee markups held earlier this year, we understand it might be added to a package bill. The Act allows complex biologic therapies to be conditionally approved without phase III trials and prescribed to patients based on studies in a limited population without proof that the new therapy actually works. If this Act passes, it could lead to the Centers for Medicare and Medicaid (CMS) wasting billions of dollars on medications that were approved by the FDA but do not work.

The Alliance for Regenerative Medicine (ARM) does not support the REGROW Act, because those researchers want  “to ensure access to safe and effective regenerative medicine therapies without putting patients at risk, disadvantaging American therapeutic developers and potentially damaging a very promising field of medicine”(emphasis added).[7]  In her recent article about stem cell research in the New England Journal of Medicine, University of Wisconsin law professor and biomedical ethicist R. Alta Charo said, “The best way to find safe effective cures is through the careful steps of clinical trials and treatment monitoring.”¹¹

 For the remaining Senate FDA-NIH bills, we urge you to only support them if they provide mandatory new funding for the National Institutes of Health (NIH) and the Food and Drug Administration (FDA).   If mandatory funding is not included, we strongly urge you to vote against the bills.

 Funding for NIH & FDA

Prior to last year’s $2 billion one-time funding increase, NIH’s funding remained flat for more than a decade (about $30 billion per year).¹² Unfortunately, the Cures Act $9 billion increase in NIH research funding is still below what it would have been had Congress not previously allowed NIH’s annual budget to stagnate.¹³

The Cures Act also would provide the FDA with $550 million in new mandatory funding over five years, but the amount of money pales to the additional workload that the Act assigns to the FDA. New FDA Commissioner, Robert Califf, has warned that Congress needs to provide the FDA with an “adequate and stable source of funding” for the mandates in the legislation.¹⁴

Adequately funding NIH is essential if we are serious about the Vice President’s Cancer Moonshot, precision medicine, and efforts to find treatments for Alzheimer’s disease, autism, depression, schizophrenia, addiction and other maladies.¹⁵  Underfunding the FDA is likely to slow the approval of new medical products because the agency’s workload has been significantly increased with unfunded mandates.

Conclusions

Members of our coalition agree with most Americans in opposing regulations that would speed the approval of medical products by lowering FDA’s safety and effectiveness standards. We strongly urge you to oppose any bill that weakens FDA’s safety and effectiveness standards, and to ensure that any legislation aimed at improving medical treatments include new mandatory funding for the NIH and the FDA. 

AMWA

Breast Cancer Action

Center for Medical Consumers

Connecticut Center for Patient Safety

MAME

MedShadow Foundation

MISSD

MRSA Survivors Network

National Center for Health Research

National Consumers League

National Organization for Women

National Physicians Alliance

National Women’s Health Network

Quinolone Vigilance Foundation

The TMJ Association

Washington Advocates for Patient Safety

WoodyMatters