September 19, 2016

Comments of Patient, Consumer, and Public Health Coalition

 on “Evaluation and Reporting of Age, Race, and Ethnicity Data in Medical Device Clinical Studies: Guidance for Industry and Food and Drug Administration Staff”

Docket No. FDA-2016-D-0734

Members of the Patient, Consumer, and Public Health Coalition have substantial concerns about the weaknesses of the draft guidance “Evaluation and Reporting of Age, Race, and Ethnicity Data in Medical Device Clinical Studies.”  It does not go far enough to improve the proportion of medical devices that are as safe and effective as possible for all subgroups included in an indication for approval.

The purpose of the guidance is to outline FDA’s expectations for the evaluation and “reporting of age, race and ethnicity [subgroups] data in medical device clinical studies.”  FDA evaluated the subgroup “sex” in a previous guidance.[1] 

We agree with the guidance’s recommendation that “clinical trials include diverse populations that reflect the intended populations,” but strongly disagree with the caveat “especially when clinically meaningful differences in safety, effectiveness…or benefit-risk profile are expected across these groups.”   We oppose that caveat because in many cases when the risk-benefit ratio differs, those differences were not expected.

We agree that sponsors (device makers) “should develop a strategy to enroll diverse populations.”  We also agree that these data are needed because “historically many medical device clinical studies” have not included subgroups in proportions that reflect “disease distribution in the affected [subgroup] population.”[2]  In fact, members of our coalition have worked on this issue for many years. For example, at a 2014 FDA AC meeting for a weight-loss device, National Center for Health Research (NCHR) noted that even though four out of five Black women in the U.S. are overweight or obese and Hispanic women are more likely to be overweight compared to White women as well, the clinical trial was 93% White. Only 11 patients were Black and only 2 were Hispanic.  Although the Advisory Committee members voiced their concerns about the mostly white sample, they voted for approval of this device anyway.  This shows two problems: 1) the FDA is not requiring diversity in clinical trials and 2) when companies fail to include sufficient numbers of minority groups to conduct subgroup analyses, the FDA is not providing instructions to their Advisory Committee members that such diversity is essential for FDA approval and for public health.

Several of our members also spoke at the April 2014 Section 907 hearing on this issue.  We noted the importance of including women, minorities and the elderly in clinical studies of safety and effectiveness for drugs and devices. We recommended that subgroup analyses be used as a basis for approval, in labeling decisions, and that the information be made available to patients and providers.

This draft guidance addresses many of the concerns raised previously by coalition members, and we are concerned that the FDA has continued to approve devices that were not analyzed in subgroup analysis proving that benefits outweigh the risks for women, people of color, and people over 65.  If FDA continues to approve/clear devices without subgroup data, then many medical device companies will ignore this guidance, as they often have in the past.  While guidances are not enforceable, FDA has the authority to refuse to approve medical products that have not been adequately tested on representatives of the population that will rely on them.  For example, if the FDA clearly states that a sponsors’ applications will be rejected — or perhaps approved only for the population that was adequately tested in subgroup analyses of safety and effectiveness, we are confident that companies will find a way to comply.

Below are our specific comments on the guidance:

Analyses should focus on each subgroup independently

Analyses should focus on whether a device is safe and effective for each subgroup independently, rather than whether there is a difference between groups.

Differences in safety and effectiveness between subgroups are much less important than whether benefits outweigh the risks for each subgroup.  For example, in a study of 20,000 patients, it is possible that a small difference between racial groups would be statistically significant for a device that is very effective for both all races.  But, for patients, that small difference would not matter.  What matters is not that they differ, but whether or not the device is useful for all racial groups.

Another reason why comparisons between or among groups is not sufficient is that smaller sample sizes result in wider confidence intervals. Therefore, the subgroups with fewer patients have a greater chance of appearing not significantly different from the other groups.  This would mask much of the meaningful information about safety and effectiveness in specific subgroups.  The guidance recommends device makers engage in “consultation with FDA” when sample sizes are not large enough.  This unfortunately will result in subjective case-by-case reviews, which can result in bias as well as being labor and resource-intensive for CDRH, which is under-funded. If the FDA believes such case-by-case reviews are needed, industry should pay for them through generous user fees.  Such “consultations” should not be funded by appropriations that are already inadequate for CDRH.

Analysis by age

The guidance notes that different age populations are “often underrepresented” in clinical trials for medical devices, and it cited the 2013 FDASIA 907 report that found “only 40%” of approved PMAs “reported an age based analysis of outcome data” and that age information was inconsistent and not detailed enough.  Medical device companies must provide more and better data. The guidance states that “older patients may have age-related covariates” (less bone density, slower metabolisms, and digestion issues) “that could affect the performance of medical devices.”   It also notes that pediatric subgroups are affected differently by medical devices “due to the size of the implant,” and that they are more “radiosensitive than adults.”

We agree with the guidance’s recommendation that studies should use more discrete age categories in performing subgroup analyses.  Even though FDA does not define a specific age for the geriatric population, we strongly urge that devices intended to be used by older patients should include an analysis of patients who are over 65 separately from younger adults.  FDA has expressed an interest in harmonizing with the Centers for Medicare & Medicaid Services (CMS), and since most Medicare patients are 65 and older, research evidence that a device is safe and effective in this age group would benefit patients, companies, and CMS.

Analysis by race, and ethnicity

The guidance notes that the U.S. population is becoming more diverse, yet subgroup representation in clinical trials “remains a challenge and inconsistent analysis and reporting contributes to persistent lack of publicly available data on device performance in diverse ethnic and racial groups.” The FDASIA 907 Report showed that “only 27% of the studies reviewed contained a race or ethnicity subgroup analysis and only 16% had public statements” regarding the subgroups.  Recent analyses by the National Center for Health Research found that this continued to be a problem for devices FDA reviewed in 2015.  It is critical that racial and ethnic subpopulations be adequately represented in clinical trials in order to ensure that the tested product is safe and effective for all the subpopulations that are likely to use that product.

Postmarket submissions

The guidance states that “consideration should be given to whether market approval/clearance is supported for the general population, with postmarket studies to gain further information regarding any observed…subgroup differences.” We urge FDA to require subpopulation data be analyzed before the device is marketed and that the focus be on benefits outweighing risks for each subgroup, rather than comparing subgroup differences.

Once a device maker has its product on the market, there is no incentive for them to do postmarket studies in a timely manner (or to complete them at all) since their device has already been approved/cleared by the FDA.  Additionally, the guidance notes there are “concerns about disproportionate dropout and loss to follow-up [which] are potential barriers to diverse study representation of minorities and older patients.”  For that reason, companies need to create incentives to keep patients in their studies.  If those studies are not completed appropriately, the FDA should rescind approval.

Unplanned subgroups analyses

We agree with the guidance that “unplanned subgroup analyses or those with inadequate sample size are generally not considered to be adequate to support statements in the labeling regarding the safety or effectiveness of the device.”  We suggest deleting the word “generally” from that sentence.

Device labeling

We agree with the guidance that “when clinically relevant differences in treatment effect are anticipated across age, race, or ethnic groups, these effects should be considered in the study design and…device labeling.”  However, as stated above, it is not sufficient to only consider such issues when subgroup differences are anticipated – they should always be considered.  In addition, also as stated above, subgroup differences are not the key issue; what matters to patients and providers is how safe and how effective devices are for patients in each subgroup.

In addition, we are concerned that patients will never see the label for the devices implanted in their bodies (hips and knees, for example).  Even more disturbing, surgeons have told us that they do not see the medical device labels either. FDA should investigate whether or not surgeons actually see and read the device labels, or if the labels are removed before surgeons receive the devices in the operating room.

“Snapshots” for medical device trials

Although it is beyond the scope of this guidance, the FDA should consider creating an equivalent to the FDA Drug Trials Snapshots for medical devices. This would make demographic subgroup data more available and transparent to the public.

Conclusions

To ensure that medical devices intended for use by the entire U.S. population are safe and effective for all relevant subgroups, FDA needs to require device makers to include more diverse populations in their analysis of clinical trials, and needs to require that subgroups be large enough to analyze to determine how safe and how effective a device is for each major subgroup population.   If a device is not safe and effective for all target groups, then labels should say that and approval indications should be restricted to those populations for whom benefits outweigh the risks.  Otherwise, doctors and patients will not have the information needed to make decisions about whether to use the device for treatment.

We are disappointed that this guidance, like other FDA documents, continues to miss the essential issues regarding subgroup analyses: to answer the question of how safe and how effective is this device for each major subgroup.   We strongly urge the FDA to require that safety and effectiveness be analyzed separately for each subgroup instead of just comparing safety or effectiveness between or among subgroups.  Companies need to collect sufficient information to evaluate the benefit/risk profile for each subgroup independently.  That will make it possible to determine if medical devices are sufficiently safe and effective for anyone who uses them.

Without these changes, the guidance will not help ensure that patients and providers have the information they need to determine if a device is likely to be safe or effective for a wide range of patients in terms of age, race, and ethnicity.  Moreover, it is crucial that FDA hold device makers accountable by not approving devices for all Americans if it has not been proven to have benefits that outweigh the risks for all major subgroups that will use those devices.

American Medical Student Association

American Medical Women’s Association

Breast Cancer Action

Breast Cancer Consortium

Connecticut Center for Patient Safety

MRSA Survivors Network

National Center for Health Research

National Organization for Women

Our Bodies Ourselves

The TMJ Association

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

[1] Food and Drug Administration (2014).  Guidance: Evaluation of Sex Specific Data in Medical Device Clinical Studies. http://www.fda.gov/downloads/medicaldevices/deviceregulationandguidance/guidancedocuments/ucm283707.pdf

[2] Food and Drug Administration (2016).  Draft guidance: Evaluation and Reporting of Age, Race, and Ethnicity Data in Medical Device Clinical Studies. http://www.fda.gov/downloads/MedicalDevices/DeviceRegulationandGuidance/GuidanceDocuments/UCM507278.pdf

September 19, 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

The Food Additive Petition Filed by Breast Cancer Fund, Center for Environmental Health, Center for Food Safety, Center for Science in the Public Interest, Clean Water Action, Consumer Federation of America, Earthjustice, Environmental Defense Fund, Improving Kids’ Environment, Learning Disabilities Association of America, and Natural Resources Defense Council;

  [Docket No. FDA-2016-F-1253]

Members of the Patient, Consumer, and Public Health Coalition strongly support the food additive petition to amend or revoke food additive regulations regarding food processing and packaging involving specific  phthalates.[i]  We strongly urge the FDA to ban the use of these ortho-phthalates for use in the production, storage, and packaging of food.

More commonly known as phthalates, ortho-phthalate metabolites are detectable in nearly everyone in the U.S.,[ii] primarily because of the food we eat.^[iii] While exposures to specific phthalates may be low for many individual foods, they are present in a wide variety of foods and so the cumulative level is much higher.[iv]^, [v]^, [vi]

Phthalate exposure can have diverse and long-lasting harms. Phthalates such as DEHP are probable human carcinogens.[vii] Exposure before birth and during early life has been linked to numerous problems with brain development. These include Attention Deficit Hyperactivity Disorder (ADHD) related behaviors, impaired social behavior, aggression, depression, and lower IQ.[viii] Increased exposure causes reproductive problems for both sexes, including abnormal testicle development and preterm birth.[ix]

Eleven phthalates have been found to affect reproductive, developmental and endocrine health, and the remaining substances do not have sufficient evidence to judge their safety As such, it is impossible to conclude that there is “reasonable certainty of no harm.” We agree with the petitioners that phthalates should be addressed as a class because if phthalates are considered on an individual basis, one harmful phthalate will likely replace another harmful one. Phthalates contaminate food at different stages of production and storage.[x] We support the extensive scope of the petition to cover all of the steps in processing and packaging of food.

We note that government agencies have already banned or limited the use of certain phthalates covered by this food additive petition. The Consumer Product Safety Commission has banned the use of six of these phthalates from children’s toys and other products due to these health concerns for this vulnerable population.[xi] The FDA already limits/warns about the use of DEHP in medical devices[xii] and DEHP and DBP in drugs.[xiii] Clearly, the same chemicals in our food is potentially even a greater risk.

Conclusions

Our Coalition and member groups have commented or testified to the FDA on phthalates and food contact issues for several years. In 2010, members of our coalition submitted comments in support of the FDA’s proposed rule regarding allowable DEHP levels in bottled water (see Docket NO. FDA-1993-N-0259).

The National Center for Health Research’s Dr. Anna Mazzucco spoke at the December 9, 2014 FDA meeting on expanding the Redbook to enhance the safety of food and products. Dr. Mazzucco noted that “Current evaluation of food additives for carcinogenic activity is narrowly focused on genotoxic mechanisms of action.  She added that the FDA should add tests for endocrine disruption to its toxicological evaluation of food contact substances and additives to ensure that all food contact substances, both old and new, are safe.”

In summary, we agree with the March 18, 2016 letter from the Natural Resources Defense Council and other groups to the Center for Food Safety and Applied Nutrition. The letter states that “there is no longer a reasonable certainty of no harm for the food contact use of the 30 phthalates.” We echo their concerns that exposure levels to U.S. citizens of these phthalates are above the tolerance for the class of chemicals. The FDA should ban the use of phthalates for use in the production and storage of food.

American Medical Student Association

American Medical Women’s Association

Breast Cancer Action

Breast Cancer Consortium

Mothers Against Medical Error

MRSA Survivors Network

National Center for Health Research

National Consumers League

National Organization for Women

Our Bodies Ourselves

Washington Advocates for Patient Safety

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

[i] Federal Register (May 20, 2016). Food and Drug Administration, notice of petition. Breast Cancer Fund, Center for Environmental Health, Center for Food Safety, Center for Science in the Public Interest, Clean Water Action, Consumer Federation of America, Earthjustice, Environmental Defense Fund, Improving Kids’ Environment, Learning Disabilities Association of America, and Natural Resources Defense Council; Filing of Food Additive Petition.

[ii] National Health and Nutrition Examination Survey (NHANES) (October 2014). Phthalates and plasticizers metabolites- Urine (PHTHTE_G); years of content 2011-2012. http://wwwn.cdc.gov/Nchs/Nhanes/2011-2012/PHTHTE_G.htm

[iii] Consumer Product Safety Commission (July 2014). Chronic Hazard Advisory Panel On Phthalates and Phthalate Alternatives.https://www.cpsc.gov/PageFiles/169876/CHAP-REPORT-FINAL.pdf

[iv] Sathyanarayana S et al (2013). Unexpected results in a randomized dietary trial to reduce phthalate and bisphenol A exposures. J Expo Sci Environ Epidemiol. 23(4):378-384.

[v] Schecter A et al (2013). Phthalate concentrations and dietary exposure from food purchased in New York State. Environ Health Perspect. 121(4):473-479. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3620091/

[vi] Serrano SE, Braun J, Transande L, Dills R, Sathyanarayana S (2014). Phthalates and diet: a review of the food monitoring and epidemiology data. Environ Health 13:43.

4 Agency for Toxic Substances and Disease Registry (2002).  Toxicological profile for di (2-ethylhexyl) phthalate.  Update. Atlanta, GA:  U.S. Department of Health and Human Services, Public Health Service.

[viii] Ejaredar M, Nyanza EC, Ten Eycke K, Dewey D (2015). Phthalate exposure and children’s neurodevelopment: A systematic review. Environ Res 142:51-60.

[ix] Marie C, Vendittelli F, Sauvant-Rochat MP (2015) Obstetrical outcomes and biomarkers to assess exposure to phthalates: A review. Environ Int. 83:116-136.

[x] Fierens T, Van Holderbeke M, Willems H De Henauw S, Sioen I (2013). Transfer of eight phthalates through the milk chain — A case study. Environ Int. 51:1-7.

[xi] US Consumer Product Safety Commission. (July 2015). Phthalates. http://www.cpsc.gov/en/Business–Manufacturing/Business-Education/Business-Guidance/Phthalates-Information.

[xii] US Food and Drug Administration (July 2002). FDA public health notification: PVC devices containing the plasticizer DEHP. http://www.fda.gov/MedicalDevices/Safety/AlertsandNotices/PublicHealthNotifications/ucm062182.htm.

[xiii] US Food and Drug Administration (December 2012). Limiting the use of certain phthalates as excipients in CDER-regulated products. http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm330792.htm

August 9, 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 the draft guidance

Dissemination of Patient-Specific Information from Devices by Device Manufacturers

[Docket No. FDA-2016-D-1264]

Members of the Patient, Consumer, and Public Health Coalition appreciate the opportunity to comment on the draft guidance Dissemination of Patient-Specific Information from Devices by Device Manufacturers.  We generally support the draft guidance but the document needs further clarification, especially the paragraph on the Health Insurance Portability and Accountability Act (HIPAA).

The purpose of the draft guidance is to “clarify that manufacturers may share with a patient  patient-specific information” collected from devices regarding that same patient.  In other words, device companies may share with a patient the information that the device collects about him or her. The draft guidance defines “patient-specific information” as including “recorded patient data, device usages/output statistics, healthcare provider inputs, incidence of alarms, and/or records of device malfunctions or failures.”[1] We agree with FDA that providing the above information “will empower patients to be more engaged with their healthcare providers in making sound medical decisions.”¹

Content

FDA recommends that device makers take steps to avoid “disclosure of confusing or unclear information that could be misinterpreted” by patients. The draft guidance does not provide details on how device makers should accomplish this goal.  If the information from the device is summarized, key data could be omitted. Alternatively, if all data is released (e.g. via data dump), the information could be overwhelming and useless to the patient.

Information communicated to patients should be done in a manner that is easy for them to understand.  Only 12 percent of adults have proficient health literacy, according to the National Assessment of Adult Literacy.[2]  This indicates that many patients may not be able to understand information that is complicated or communicated using medical terminology. Patients benefit from interactive, simple to follow, and practical communications that are appropriate to the intellectual and social skills of the patient and the caregiver.[3]

FDA notes that device makers “may share patient-specific information…with patients at the patient’s request without obtaining additional premarket review before doing so.” FDA then cautions that additional information from devices shared with patients by the manufacturer could meet the definition of labeling and would be subject to FDA labeling regulations. Although FDA cites the labeling section of the Federal Food, Drug, and Cosmetic Act (section 201 (m)), the draft guidance does not provide an example of when information shared from a device would meet the labeling definition.

FDA states that often the patient-specific information is “accessible by the patient’s healthcare providers,” or patients may contact the manufacturer directly to obtain the information.  The advantage of receiving the information from a healthcare provider is that the information will more likely be interpreted and put in context, and the patient can ask follow-up questions.   The disadvantage is that the patient will have to pay for the appointment, and may not be able to access the information in a timely manner.

We agree with FDA that patient-specific information shared with patients should be “comprehensive and contemporary” and the information from a patient’s blood pressure device provides a good example. But again, we are concerned that “comprehensive” could become a useless “data dump.”

Context

We agree with FDA that patient-specific information should include “relevant context” so that the information will not be misinterpreted, “thus leading to incorrect or invalid conclusions.” Invalid conclusions could lead to additional tests (i.e. over diagnosis), or false negatives, which could put the patient’s health at risk. We also agree with FDA that device makers who provide patient-specific information should include information “about whom to contact for follow-up information.”

 HIPAA

The draft guidance dedicates one paragraph to HIPAA.  It notes that HIPAA protections apply to device makers to prevent the sharing of “individually identifiable health information” but the protections “are not intended to prevent a device manufacturer from sharing patient-specific information with the affected patient.”

A recent article criticized FDA’s definition of “Patient-specific information” because it “appears to be, at least in part, inconsistent with HIPAA’s definition” of Protected Health Information (PHI). The article also notes that “there are a number of instances where a device manufacturer may be a HIPAA-regulated entity.”[4] For example, if a medical device company has contracted with a covered entity (such as a doctor’s office or hospital) so that the device will transmit electronic protected health information directly to the provider, compliance with HIPAA requirements is mandated.[5] This type of scenario is not addressed in the draft guidance.

Others have noted that the guidance appears to offer an incorrect interpretation of HIPAA when it states that device manufacturers are prevented under HIPAA from sharing this information with covered entities, such as health plans and health-care providers that electronically transmit health data, without the patient’s consent.[6]  We agree  that HIPAA was never meant to prohibit patient data collected by devices from being shared with the patients’ own physicians. Clarification of these issues is needed.

Also, nothing is mentioned about encrypting sensitive personal health information, or the risk of data breaches.  The draft guidance should recommend steps device makers can take to mitigate the risk of data breaches, and to make sure the information is not compiled in any databases that are shared with health plans or healthcare providers.

Conclusions

We generally support this brief draft guidance but the HIPAA section needs clarity, and Content section needs more details on how device makers can avoid disseminating “confusing or unclear information” to patients.

 American Medical Women’s Association

Breast Cancer Action

Connecticut Center for Patient Safety

MRSA Survivors Network

National Center for Health Research

National Consumers League

Our Bodies Ourselves

The TMJ Association

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

[1] Food and Drug Administration (June 10, 2016).  Dissemination of Patient-Specific Information from Devices by Device Manufacturers; Draft Guidance of Industry and Food and Drug Administration Staff. http://www.fda.gov/downloads/medicaldevices/deviceregulationandguidance/guidancedocuments/ucm505756.pdf

[2] Quick Guide to Health Literacy. US Department of Health and Human Services. https://health.gov/communication/literacy/quickguide/factsbasic.htm

[3] Schooley B, San Nicolas-Rocca T, Burkhard R. Patient-provider communications in outpatient clinic settings: a clinic-based evaluation of mobile device and multimedia mediated communications for patient education. JMIR Mhealth Uhealth. 2015 Jan 12;3(1):e2. http://www.ncbi.nlm.nih.gov/pubmed/25583145

[4] Weinrieb JM, Weeda JM (June 15, 2016). FDA Publishes Draft Guidance on Dissemination of Patient-Specific Data—But Doesn’t Say Much About HIPAA.  OFW Law. http://www.ofwlaw.com/2016/06/15/fda-publishes-draft-guidance-dissemination-patient-specific-data-doesnt-say-much-hipaa/

[5] Hartford, J (August 25, 2015). Are your medical devices HIPAA compliant? MDDI DeviceTalk. http://www.mddionline.com/blog/devicetalk/are-your-medical-devices-hipaa-compliant-08-25-15.

[6] Williamson MD (June 13, 2016). FDA Guidance on Device Data Sharing Aligns With HIPAA: Attorney. Bloomberg BNA. http://www.bna.com/fda-guidance-device-n57982074036/

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