FDAMap News 2015

Newsletter - December 10, 2015 (Highlight: FDA Seriously Concerned about Lab Developed Tests and Wants to Regulate Them Strictly, Best Practices for Meetings with FDA: New Guidance, “Old” Information)

Newsletter - December 03, 2015 (Highlight: New Rules from Department of Justice to Target CEOs, FDA Slams Company "Healthy" Label, FDA Encourages Resolving Disputes with Sponsors)

Newsletter - November 19, 2015 (Highlight: Is the FDA at Fault for Allowing Drugs Made in India Despite Multiple GMP Violations, Clinical Trial Results Remain Under-Reported Publicly)

Newsletter - November 12, 2015 (Highlight: GMP Compliance at Indian Drug Manufacturers Questioned by RAPS, FDA Regulation of E-Cigarettes Creates New Opportunities)

Newsletter - November 05, 2015 (Highlight: Tobacco Regulation on Steroids-FDA Comes Down Hard on Tobacco Retailers, Want to Know What Trials Supported FDA Approval)

Newsletter - October 29, 2015 (Highlight: Are Indian Drug Manufacturers Really That Bad in GMP Compliance, Compounding Expensive FDA-Approved Drugs to Reduce Price, Research Productivity: Who Discovers More, Academia or Industry)

Newsletter - October 23, 2015 (Highlight: Human Factors to Play a Bigger Role in FDA’s Decisions about Medical Devices, Genetic Tests: Two Companies Different Stories)

Newsletter - October 15, 2015 (Highlight: Herbal Supplements Linked to Thousands of ER Visits Each Year, Study of Gender Differences in Clinical Trials, Most Cell-lines Used in Testing may be Incorrectly Identified)

Newsletter - October 8, 2015 (Highlight: Updates to GCP and US Policies for Clinical Trial Patients, Pharma Product Hopping and Product Engineering in the Limelight Again, Lack of GMP Training is Expensive: Lessons from Compounding Pharmacies)

Newsletter - October 1, 2015 (Highlight: FDA to Destroy Illegal Drugs Arriving in the US by Mail, USP Revises Compounding Pharmacy Rule to Address Sterile Drugs, Is FDA's Expedited Approval Programs Leading to Bad Drugs)

Newsletter - September 24, 2015 (Highlight: CEO Jailed for Life in Food Contamination Case, Life-Saving Drug Price Hiked Unreasonably, President Obama Appointed New FDA Commissioner)

Newsletter - September 17, 2015 (Highlight: Food Safety Comes to Fore with New FDA Rules for GMP, FDA Blocks Four New Cigarette Brands, FTC Wants FDA to Increase Homeopathic Drugs' Regulations)

Newsletter - September 10, 2015 (Highlight: Should FDA be More Flexible for Approval of Drugs for Severe Drugs, Drug Industry Lobby Group Defends High Drug Prices)

Newsletter - September 3, 2015 (Highlight: GCP Inspectors Need to be Highly Qualified - EMA, Electronic Informed Consent in Clinical Trial is Opportunity or Liability)
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Newsletter - August 27, 2015 (Highlight: FDA Approves Practically All Market Approval Applications These Days, There is NO Viable Alternative to Animal Studies, Different FDA Divisions Follow Different Times)

Newsletter - August 20, 2015 (Highlight: Celebrity Endorsement and FDA - An Unwinnable Battle for the Agency, Female Viagra Marketing Set to Test Off-Label Sale Rules Post FDA Approval, Office of Generic Drugs Opens the Door a Bit to Get Timely ANDA Updates)

Newsletter - August 13, 2015 (Highlight: Court Goes Against FDA to Allow Off-Label Promotion...Again, GMP Issues for 3D Printed Pills Resolved But Is It Really a Big Deal, The Promise of Bacteriophage Therapy Rekindled But Hurdles Remain)

Newsletter - August 6, 2015 (Highlight: Abuse Deterrent Technology Comes of Age in Opioid Formulation, Medical Device Labeling in FDA's Cross Hair, Hacking into a Remote-Controlled Device is Not Science Fiction Anymore)

Newsletter - July 30, 2015 (Highlight: High Levels of Drugs Found in Water Supplies Worldwide, Will Clinical Trial Data Sharing Hurt Innovation, FDA Requires Drug Companies to Update Analytical Procedures as Part of Life-Cycle Management)
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Newsletter - July 23, 2015 (Highlight: EMA to Follow FDA-Like Practice to Advice on Post-Marketing Study Design, FDA Wants to Know Drug Side-Effects by Google Search, FDA Rapidly Updating its Policies to Regulate Medical Software to Match the Technological Realities)

Newsletter - July 16, 2015 (Highlight: Should Prescription Drugs Cost be Controlled in the US, SOP Deficiencies and Documentation Errors Dominate EMA GCP Audit Findings, Manufacturers of Biologics to Increasingly Use Single-Use Technologies)

Newsletter - July 9, 2015 (Highlight: Unblinded Studies are Biased Even if the Researchers are Well-Intentioned, FDA Expects Drug Manufacturers to Intimate 6 Months in Advance of an Upcoming Drug Shortage, US FDA and Interpol Seize 21 Million Fake Medicines)

Newsletter - July 2, 2015 (Highlight: The Breakthrough Designation Can be Withdrawn or rescinded by FDA, FDA Inspectors to Find Major Issues with GMP Compliance by Paying Close Attention to Details)

Past News

Look below for past news content from FDAMap.

Right to Keep Confidential Reasons for Rejection of Drug Approval by FDA Questioned
Posted on: Friday, June 26, 2015

Whenever a new drug is disapproved, FDA issues a complete response letter (CRL) to the manufacturers citing all the reasons why it was rejected. These letters contain details of the applicant’s development program with specific deficiencies identified and potential solutions offered. The CRL becomes the roadmap for the applicant to satisfy FDA’s concerns and eventual approval. Due to the extremely confidential nature of this information, companies typically only disclose portions of the CRL relevant to their investors and the public. Due to the proprietary nature of the information, a given company has the right to not disclose any portions they believe to potentially hurt their competitive edge. In an article published this week in The BMJ, several FDAers challenge this right.

Expert Opinion: Mukesh Kumar
VP, RA, Amarex Clinical Research

The authors of the article reviewed 61 CRLs issued between August 11, 2008 and June 27, 2013 (48 for NDAs and 13 for BLAs) to compare the proprietary information in those CRLs with the respective applicants’ public statements regarding the CRL. The authors attempt to highlight several critical pieces of information included in the CRLs regarding the reasons for rejection of the application and lack of such information in the applicant’s public disclosure. The articles raises serious questions about the right of the public to know why a drug is rejected and makes an altruistic claim that public disclosure of the complete CRL either voluntarily by the company or by changing the law to allow FDA to disclose it would somehow help drugs come to market faster. However, the article ignores the obvious loss of competitive edge to the company whose product got rejected and the importance of the CRL in allowing a given company to meet FDA’s specific concerns without providing tips to its competition about its development program.

The article also misdirects the real question of transparency; the information of such nature is not intended for the general public and patients as it seems to be indicating but for other companies who are developing similar therapies. It is intended to help other learn from someone’s mistakes. Is it fair for a company to make it’s competition better? What about the company’s obligations to its investors regarding protecting their assets? This is not an issue of greater transparency in FDA’s processes but rather of the importance of confidential interactions between FDA and companies.

The core element of these interactions is that companies be able to discuss all aspects of their product with FDA without fearing loss of confidentiality. Without a promise of great confidentiality, companies will not disclose key elements of their program to FDA due to business reasons severely hampering innovation and new drug development. The authors of the articles have their faith misplaced. FDA has been frequently accused of less transparency; and FDA in turn has blamed the industry of too much secrecy. This article is another effort by the FDA to move the heat away from itself. Impact of it will likely be marginal as neither of the parties can really change the dynamics of the process of FDA-Industry interactions.

Additional reading: http://goo.gl/n8PcuL

Google Changes SEM Policies for Drug Ads to Meet FDA Requirements
Posted on: Friday, June 26, 2015


In its efforts to rein in drug advertisement in the digital age, FDA has published several guidance documents and rules to clarify and advise about acceptable marketing practices.

Expert Opinion: Mukesh Kumar
VP, RA, Amarex Clinical Research

There is a guidance on use of website content and twitter among others that advise about FDA’s expectations. However, there is little advice from FDA about adequate digital ads such as those on Google search engine. At the same time FDA has been taking action against companies it deems to be practicing unacceptable digital advertisements. The first such action by FDA was in March 2009 when FDA sent simultaneous Warning Letters to 14 companies for illegal digital ads for 48 products. These letters explicitly referred to SEM ads running on Google, and one cited organic search listings on Yahoo! The violations identified included omission of risk information, overstatement of risk, using misleading or inaccurate product name, and not identifying the indication properly. At that time, drug companies pretty much stopped using SEM ads. But over time, the drug companies found a way to be compliant by using Reminder ads and Redirecting ads. However, there are increasing concerns about the compliance of these digital ads as well. To address the concerns, Google announced two significant changes this week to the way paid search engine advertising works for pharmaceutical products. The first change affects only black box drugs and will take effect beginning July 20, 2015. The second affects redirecting ads and will take effect in January of 2016. This is to be compliant to the FDA guidance on online ads with limited space setting. Under the new policy, starting 20 July 2015, Google will require all drug ads to follow the standard ad format which will include the brand and generic name as well as a "Please see" statement directing users to the full PI including boxed warning. Starting January of 2016, Google will not allow any redirected ads for drug ads. These policies will apply to all drugs, biologics and medical devices regulated by the US FDA, and will be Google worldwide policy for such ads. This is bound to update all SEM ads for drugs. It is also expected to affect ads placed on other search engines such as Yahoo and Bing.

FDA’s Announcement of Negative Audit Findings Lead to Similar Actions by Other Regulators
Posted on: Friday, June 26, 2015

Expert Opinion: Mukesh Kumar
VP, RA, Amarex Clinical Research

When FDA audits a company and find smajor deficiencies followed by publicly disclosing its findings, other regulatory agencies in the rest of the world also take notice. Hospira learnt it the hard way recently when Health Canada banned products manufactured at Hospira’s facility in Italy specifically citing the “reliability of the laboratory data” and FDA’s warning letter for its decision to ban the drugs. Although the Canadian agency’s decision doesn’t impact all the products produced by Hospira, it’s surely going to point at the irregularities prevailing at many of its plants. It’s also going to impact the proposed buyout deal by Pfizer, which is worth $16 billion. Hospira has been receiving FDA warnings letters since 2013 and enforcement action is likely to happen at two of its facilities, one in the U.S. and another in Australia. The issues aggravated to such a high degree in July 2014 that FDA had to ask the company to immediately undertake a comprehensive assessment of all its global manufacturing units and to make sure that they were compliant with FDA requirements. It was followed by several product recalls by the drug manufacturer. This is not the first time that FDA’s negative audit findings led to regulatory actions by other regulators. Similar fate awaited several generic drug manufacturers in India and China where severe FDA action led to similar actions by regulators in Europe, Australia and Canada. One more example of why one should pay attention to FDA’s audits, not just for doing business in the US but to assure compliance with global markets.

FDA Approves Brio Neurostimulation System, the Second Brain Implant that Brings Relief from Parkinson’s Symptoms
Posted on: Thursday, June 18, 2015

FDAMap Expert Opinion

The US FDA has approved the second implantable medical device for the treatment of symptoms of Parkinson’s disease. The device, Brio Neurostimulation System, provides relief from essential tremor, shaking and difficulty in walking and maintaining balance, that severely affect the quality of life of patients with Parkinson’s. There are several significant regulatory observations that can be made for this device’s approval. This is the first such device approved in 18 years and involved vigorous clinical trials to support the market approval. Two large clinical trials in 263 patients with advanced symptoms of Parkinson’s were operated to install the device and patients took both their regular drug treatments along with the device. The device was approved despite some severe side effects including intracranial bleeding since there are no treatment options to the target patients and the benefit outweighed the risk. The device is powered by a battery that met a more robust recent FDA requirement for batteries.

This electronic device can be implanted under the skin of the upper chest and is connected with wires to the electrodes which can be planted deeper into the specific brain locations, from where it sends electronic pulses. The Brio Neurostimulation System is developed for the cases, where medication becomes partially ineffective and patients doesn’t get adequate relief from its symptoms. It’s one of the best ways to manage the symptoms of Parkinson’s, given the untreatable nature of the disease. Review of the clinical trial design and FDA approval package of this device promises to be a great learning experience for all device clinical trial sponsors.

Source: http://goo.gl/ZG6DRT

Supporters of Right-To-Try Legislation Sue FDA to Release Documents Related to Ebola Drug Use during Last Year’s Ebola Outbreak
Posted on: Thursday, June 18, 2015

FDAMap Expert Opinion

The Goldwater Institute, a think tank lobbying for the expanded access to experimental drugs, commonly known as the Right-To-Try Legislation, sued FDA to disclose the regulatory processes used to release an experimental Ebola drug to a few patients in the US during last year’s Ebola outbreak. In August 2014, FDA allowed use of Zmapp, an experimental drug being developed by the San Diego company Mapp Biopharmaceuticals, in 2 patients infected with Ebola virus. Both patients fully recovered from Ebola infection. It is widely accepted that the drug was made available under the compassionate use IND pathway but both the FDA and Mapp Pharmaceuticals have been secretive about the exact process used. FDA is bound by confidentiality rules since the compassionate use IND is a proprietary document that cannot be publicly disclosed by the Agency, and the pharma company obviously wants to closely guard its secret program from competition. However, in the process, patients who want access to other experimental drugs on a compassionate basis, and their supporters such as The Goldwater Institute, want to learn more about the regulatory precedence behind the compassionate IND review and approval process. It is widely believed that this suit will fail in the courts as asking FDA to illegally disclose proprietary documents could potentially open the floodgate to similar petitions for other drugs making the entire FDA confidential review process moot and subject to severe criticism. The law suit is erroneous in claiming that the FDA (by extension the Federal Govt.) is keeping it secret, while in fact it is the company which holds the key to the information.   

Since early 2014, 22 states have passed the so-called "Right to Try" laws with similar bills at various stages of review at the other 28 states. These laws allow terminally ill patients access to experimental treatments more easily. The hope is that patients may be able to use potentially life-saving treatments before their approval by FDA that could take years. These state laws intend to further promote FDA’s compassionate use pathways to make it faster and easier for patients to obtain experimental therapies which they cannot get in a clinical trial setting. While the spirit of these laws is noble, they do create a severe challenge to the impartial regulatory review process and potentially forces companies to provide drug supplies to patients outside of ongoing clinical trials and could hinder the innovation process critical to make drugs available to everyone.

FDA Mistakenly Widened the Market for a Rare Sleep Disorder Drug: A Consumer Group
Posted on: Thursday, June 18, 2015

FDAMap Expert Opinion

In the first quarter of 2014, a drug Hetlioz was approved by the FDA. It’s used to treat non-24 sleep-wake disorder, it’s a rare health condition related to sleeping issues that completely offset the internal body clock. However, according to a consumer advocacy group the agency mistakenly widened the market beyond its anticipated limits. In fact, on the label, it was mentioned that it was intended only for patients who are also blind, but this script was actually omitted. 

The FDA realized its mistake in the latter half of the year 2014. But instead of correcting the product labeling, the agency issued a second approval letter. In this letter, it was mentioned that that the original letter contained an error about the approved use, but they committed another mistake by changing the description of the approved use to match the incorrect product labeling, according to Public Citizen, the consumer group.

According to the consumer group’s Health Research department the FDA has allowed a potentially dangerous medication to be given to people, for whom there was no sufficient evidence that it was safe and effective and this is the failure of the agency.

This mistake was compounded by the fact that FDA took a reverse decision to further expand the approved indication and it was to recommend it to non-blind individuals, rather than correct the grave error made by the agency.

Source: http://goo.gl/z9PYi9

FDA Advisory Committee Recommends Limited Approval of Two New Cholesterol Lowering Biotech Drugs with Reservation
Posted on: Thursday, June 11, 2015

FDAMap Expert Opinion

Cholesterol lowering is linked to lower risk of cardiac episodes and is very well managed by treatment with a class of drugs called statins that include Lipitor, Zocor, etc. Lipitor and other statins are now available as cheap generic drugs and have a very well-established safety and efficacy profile. So, there was obvious skepticism to a new class of injectable cholesterol lowering drugs developed by drug giants Sanofi and Amgen. Both Amgen and Sanofi have each developed monoclonal antibody products for control of bad cholesterol in patients who do not respond well to statins alone. Both biological drugs work by blocking PCSK9 that interferes with liver’s ability to clear LDL cholesterol (the bad cholesterol). The drugs are considered as the first major breakthrough in research since the launch of popular statin drugs in the 80s. Both drugs dropped bad cholesterol level significantly without any safety concerns. FDA scientists, however, opined that the approval should be withheld till further safety studies on these drugs have not been completed. Previously such drugs have been linked to higher rates of heart problems and death in patients in the studies. The FDA Advisory panel agreed that the additional safety of these products should be completed but recommended their immediate approval for those patients whose bad cholesterol is not managed with statins alone due to genetic diseases. The limited approval will provide earlier access of these new treatments to patients who may benefit the most, while limiting their use in general population. FDA is expected to make a final decision in the next month or two for both. Although FDA is not bound by law to accept the recommendations of the Advisory Committee, traditionally it does agree with the recommendations, and most analyst believe that these drugs will be approved for treatment of patients with genetic diseases making them resistant to statins. From a practical point of view, these drugs may be used off-label by other patients. We should see insurance battles for availability of these new very expensive therapies in the age of abundant generic statins. We will keep you posted.

Source: The Washington Post 

NIH Drug Production Facility Found in Gross Violation of GMP
Posted on: Thursday, June 11, 2015

FDAMap Expert Opinion

No one is above the law, including government run facilities. The National Institutes of Health (NIH) facility in Bethesda, Maryland, which manufactures injectable drugs for clinical trials being conducted at NIH hospitals with NIH funding, was found in violation of several GMP regulations by FDA’s inspectors. The deficiencies identified include albumin vials used for administering interleukin to be contaminated by fungus and several documentation errors during an FDA audit that spanned almost 10 days in May. According to the report, the facility has little or no arrangement to prevent contamination risks to sterile drugs, the ventilation system is faulty and quality control is inadequate. The FDA investigators found other gross quality violations as well including the practice of processing sterile drug products with exposed wrist skin by an employee, who had long and exposed facial hair. These deficiencies specifically applied to the sterile drugs and did not apply to non-sterile drugs; however, since the practices were linked to not following standard operating procedures (SOPs), lack of training, and poor facility design, the concerns raised have broader implication. FDA is reported to be quite concerned about the quality control issues detected at the center despite the NIH statement that the patients on whom vials were administered were being watched closely and no sign of infection was observed. Francis Collins, the NIH director reacted with concern and termed the situation as unacceptable and troubling. He assured FDA that he will personally look into the matter that is directly linked to the safety of patients. FDA has increased it enforcement of the drug manufacturing facilities following a similar incident in New England Compounding Center compounding center in 2012, where contamination led to fungal meningitis and killed 64 people. This incidence emphasizes the importance of training in SOPs and GMP for all personnel involved in handling, production, packaging, and dispensing of drugs used in clinical trials and healthcare.

Female Viagra May Finally Get FDA Approval: Third Time is the Charm 
Posted on: Thursday, June 11, 2015

FDAMap Expert Opinion

After getting rejected twice by FDA and once by the independent Advisory Committee, the female libido drug flibanserin, commonly called Pink Viagra, finally won recommendation for approval by the Advisory Committee with FDA’s decision coming in August. The drug has very limited benefits with clinical trial participants expressing one half to one additional sexual episode compared to placebo. The drug causes serious side effects such as nausea, dizziness and fatigue, linked to certain other medication and alcohol consumption. The drug also boosts dopamine, and lower serotonin leading some increase in appetite and feelings of satiation. But the advisory panel opined that something is better than nothing. Flibanserin was originally being developed as an anti-depressant but was found to increase female libido, encouraging the developer, Sprout Pharmaceuticals, to change track mid-development and target low female libido in post-menopausal women. The key argument made at the advisory committee was lack of any treatment for female sexual disorder with Sprout even accusing FDA of gender bias against this drug compared to the standards used to approval Viagra for male sexual performance almost 17 years ago. The argument appears to have moved the panel. We will know in 2 months if that was enough to move FDA as well.

FDA to Require Mandatory Electronic Submission of Most Applications 
Posted on: Thursday, June 4, 2015

FDAMap Expert Opinion

FDA announced a much anticipated schedule for mandatory electronic submission of most market approval applications (NDA, BLA, ANDA, DMFs, etc), and INDs. In a new Guidance Document released on 15 May 2015, FDA will only accept NDA, BLA, ANDA, and Master Files via its electronic submission gateway (ESG) in the CTD format starting 15 may 2017, and not accept any paper INDs starting 15 may 2018. At present, electronic submission of an application to the FDA is optional with the applicant choosing to submit either paper documents or electronically via the ESG. Although, in the last few years the percent of market approval applications submitted via ESG have steadily increased with more than 80% of market approval applications submitted electronically in the year 2014, there are still a few sponsors who prefer paper submissions. FDA has been encouraging and supporting increased electronic submissions by publishing several guidance documents, presentations at conferences and workshops, and providing application-specific suggestions to sponsors, however by the dates listed above, FDA expects the sponsors to fully transition to electronic submissions. However, this rule does not apply to non-commercial INDs such as investigator-lead INDs, emergency use INDs, and treatment INDs, which will still be accepted in paper format, although sponsors of those INDs will have the option to submit electronically if they want. Sponsors of IND and market approval applications to FDA now have a strict deadline by which to become proficient in all aspects of electronic submissions as deficient application will be automatically rejected by FDA and will not even be reviewed. This rule adds to the ones that already exist for mandatory electronic submission of medical device reporting, drug and biologic adverse event reporting, and promotional labeling and advertisements. 

FDA Wants to Study Personal and Social Aspects of Drug Ads 
Posted on: Thursday, June 4, 2015

FDAMap Expert Opinion

Direct-to-Consumer Ads are targeted to individual patients and try to address issues that affect a given patient highlighting the benefits and risks of drugs. The assumption usually is that a patient will make his or her own decision regarding pursuing prescription of the product in the drug advertisement. However, in real life, patients likely discuss these ads with their families and friends, with the spouses playing a major role in the final decision. For example, a couple may view an ad together and discuss drug benefits, side effects, and risks before the affected spouse decides to pursue the prescription with his or her physician. The spouse may influence if a patient decides to use a drug despite the side effects or may take a more conservative approach. These social interactions are of great interest to FDA to understand how drug ads play out in a real-life setting as these have important public health implications. To understand social interactions post drug ads, FDA wants to conduct a study to examine differences between consumers viewing prescription drug ads with a spouse versus alone. When this study was announced there were several concerns raised by the industry as to how the data generated from such study will be used. Some of the concerns were the legal and practical hurdles to applying data about perception of a drug ad’s impact when viewed by patient alone or with his/her spouse, applicability of the conclusions of the study in real world setting where there is no reliable data on the influence of spouse in the final decision other than anecdotal data, the design of the study to remove bias, and validity of the scales used. From public health point of view, it’s a troubling fact that the spouses can influence the buying decision regardless of whether the drug has side effects or not. The role one’s health condition and the age plays in decisions regarding drug ads should also be studied. However, FDA brushed off all concerns from the industry and is forging ahead with this study. We will keep our fingers crossed for the conclusions of the study and its impact on the rules governing drug ads.

Article Source: http://goo.gl/kqWYXI

US Congressman Challenges FDA’s Untitled Letters
Posted on: Thursday, June 4, 2015

FDAMap Expert Opinion

FDA routinely uses “Untitled Letters” which are akin to Warning Letters but are issued when FDA does not have a clear violation description since these violations were identified by measures other than an audit. These letters which are often released to the public at the same time they are sent to the accused company could have a huge negative effect on the company under attack by FDA leading to loss in revenue, valuation and huge legal expenses. The US Congressman, Tim Murphy (R-PA) recently took FDA to task for issuing Untitled Letters without due process. In a letter to the FDA’s active Commissioner, Mr. Murphy raised several concerns about FDA’s practice and asked FDA to answer 9 questions to clarify and justify its process. These include definition of the criteria for issue of Untitled Letters consistently across various FDA offices, criteria for public posting of such letter prior to giving the affected company chance to respond, what is FDA’s motive for releasing such letters publicly, if such letters are used to announce new rules or practices, and does FDA understand and appreciate the potential impact such letters could have on the affected companies. Now that sets us up for an interesting response from FDA and a high impact Congressional Hearing. We will keep you posted.

FDA Encourages Adaptive Trial Design for Medical Device Clinical Trials: New Draft Guidance Provides Similarity to Drug Guidance

FDAMap Expert Opinion

On May 18th, FDA issued a draft guidance on Adaptive Design for Medical Device Clinical Studies. This is the first time FDA formally endorsed the use of use of adaptive clinical trial design for medical devices. This guidance follows a previous guidance for use of adaptive clinical trials for testing drugs and biologics released more than 5 years ago. Together these two guidance clarify any doubts one may have for use of adaptive trials for all FDA-regulated products.

Adaptive trials have become very popular for drugs and biologics in the last few years due to the potential to reduce resource requirements and/or increase the chance of study success. However, such trial design is not used as often for medical devices due to misunderstanding of FDA’s expectations. This guidance clarifies several issues such as when to use such trial design, the various types of adaptive designs acceptable for medical device trials, and ways to ensure trial integrity and data reliability. Unlike drug trials where FDA discourages adaptations in registration trials, it encourages such design for pivotal studies to support medical device approval. This is a welcome change. FDA strongly recommends that the sponsors of adaptive trials meet and discuss the design with FDA before implementation. Discussing the plans, proposed interim analyses, and statistical design with FDA in a meeting could greatly increase the odds of success in execution of such innovative trial designs.  

Article Source: Adaptive trials in Medical device guidance

Adaptive trial in Drugs and Biologics

To attend our upcoming workshop to learn everything about adaptive clinical trials, visit our website. 

FDA Explains Why Many Cancer Drugs Fail

FDAMap Expert Opinion

In an article published this week in Nature Drug Discovery, FDA senior officials reported that of the cancer drugs that failed to gain market approval in the last decade, about one-third were rejected by FDA due to defects in the clinical trial design, while the rest were unsuccessful  because the drug failed to show FDA-acceptable efficacy in treating the disease. FDA officials discussed in details the conditions that lead to the negative FDA decision. The authors emphasized that most of these rejections could have been avoided by having timely meetings with the FDA throughout the development program. Meetings with FDA can be used to uncover potential deficits in drug development programs and discuss strategies to avoid painful outcome of application rejection. This is not the first time FDA has emphasized the importance of formal meetings. There also have been independent statistical analysis of FDA’s decisions that established a direct correlation between the frequency of meetings with the FDA and the approval decisions. This new article does not state any new surprising findings but only a time-tested fact about FDA’s desire to be heavily involved in the development of new drugs. To get a free copy of this article, write to [email protected].  

Article Source: Article in Nature Drug Discovery

To attend our upcoming workshop on how to prepare for FDA meetings, visit our website.

Regulations on Fixed-Dose Combination and Co-Packaged Drug and/or Biological Products Simplified

FDAMap Expert Opinion

FDA has proposed some amendments in the existing regulations on over-the-counter drugs and fixed-combination prescription. According to the current regulations, it is the responsibility of the sponsor to make sure that in a fixed combination drug, each of the ingredients should make some contribution towards the claimed effects of the product. The proposed regulation would simplify the existing regulations on over-the-counter combination and prescription drugs. The existing policy would be codified to make it a single set of regulations. It will make the kind of studies required easier to know to make sure that the FDA requirements for combination drug are met. 

It would also be applicable to drug biological product combinations. This rule would also seek to clarify FDA’s requirements in reference to fixed-dose combinations to certain natural source drugs and certain synthetic drugs. It will also include the conditions in which FDA can waive the combination requirements for some specific drug and also the circumstances in which it can address the issues related to a Co-Packaged Drug.  

Insurance Coverage of a New Medical Device is Not Guaranteed by FDA Approval: Acid-Reflux Device Refused Coverage 

FDAMap Expert Opinion

Despite the approval given by the government, the insurers can refuse to cover a given device. This was emphasized by the case of Linx, a new medical implant for treatment of severe acid reflux. The device was approved by FDA about 3 years ago and is reimbursed by the Center for Medicaid and Medicare Services (CMS). However, most medical insurance companies still refuse to cover for this device citing lack of evidence for effectiveness. It does not seem that the manufacturer of the device published the Pharmacoeconomic analysis to support the use of this device. Pharmacoeconomic data demonstrates the financial superiority of using a given product over standard of care. This data shows that by using a given product, the overall cost of management of a given disease is reduced compared to treatment with other available options. This information is critical to support reimbursement by CMS and is used to negotiate coverage by insurance companies as well. Lacking such data, the insurance can steer patients towards standard of care. In this case, for example, data showing implantation of Linx reduces the need more expensive disease management of ulcers and other effects of severe acid-reflux. The manufacturer is in discussion with medical insurance companies and most likely is making that case. Their life would have been simpler and more profitable had they started at the same time they sought CMS reimbursement.

Article source: http://goo.gl/CHQpH6

FDA Raises Concerns Regarding Security of Software Running Medical Devices

FDAMap Expert Opinion

Certain infusion pumps such as Hospira LifeCare PCA3 and PCA5, used to supply of therapeutic and anesthetic drugs are controlled by software that communicates remotely with controllers and wireless networks. Such systems create a potential security vulnerability of hacking into the device and altering operation. Though so far there have been no reports of unauthorized device access or adverse events related to software-related device malfunction, FDA recently issued several security recommendations to health care facilities as well as end-users. These include closing unused ports, keeping the system disconnected with Internet, limiting network access, and use of administrative controls to detect any unauthorized changes to the code. FDA recommends that remote software-controlled medical device implement layered security practices, good network design practices, and continuous monitoring of traffic passing through firewalls. Safeguards to verify the drug delivery settings before starting an infusion are also recommended. These rules on software are similar to those requiring software to be treated as a standalone or connected medical device, implemented earlier. These additional recommendations provide added FDA guidance on this issue.  

Article Source: FDA’s medical devices safety communication page  

To attend our upcoming workshop on the related issues, visit our website.

Another Off-Label Claim Dispute between Industry and FDA: Amarin’s Vascepa (Omega 3 Fatty Acid) 

FDAMap Expert Opinion

FDA strictly enforces prevention of off-label promotion of products. In the recent past, there have been numerous cases of FDA’s punitive actions against companies and individuals accused of off-label promotion. US courts have repeated sided with FDA in agreeing that off-label promotion is not protected by free speech rights. Now Amarin Corporation, the manufacturer of Vascepa, an FDA approved prescription drug containing Omega 3 fatty acid, has filed a free speech case against FDA to resist restriction imposed by FDA to make off-label claims for Vascepa. The company claims that it is within its rights to promote the general health claims of fish oil and omega 3 fatty acids when marketing Vascepa. Amarin claims that while it is committed to share “non-misleading and truthful information” with healthcare professionals regarding Vascepa, it should be allowed to promote efficacy data from omega 3 fatty acids clinical trials in patients who have high triglyceride levels despite statin therapy. It also wants to make health claims that “supportive but not conclusive research shows that consumption of EPA and DHA omega-3 fatty acids may reduce the risk of coronary heart disease.” Obviously, FDA objects to use of these claims because of “non-conclusive” nature of the clinical trial data, and these claims are not included in the approved label of the drug. Independent healthcare experts agree that additional data is needed to support prevention of heart attacks/ strokes through reducing triglycerides levels. This would be another interesting case in the debate for the distinction between free speech and off-label claims. There is strong precedence of FDA prevailing in such law suits. We will keep you posted on the outcome.  

Article Source: Bio-space Breaking News

Unacceptable Reprocessing of Medical Devices: Case of Duodenoscopes

FDAMap Expert Opinion

Duodenoscopes are widely used reprocessed devices for ERCP. Improper cleaning and disinfection of duodenoscopes is the cause of several incidences of infections including MRSA episodes annually. At a recent FDA Advisory Committee meeting, the risk and safety issues related to these devices were discussed. The gastroenterology and urology devices advisory panel of FDA observed that though the rate of infections are low given the total number of ERCP cases performed annually across the US, it’s quite alarming as infections were traced despite strict compliance with the FDA recommendations for cleaning. The panel recommended the sterilization or using newer more efficient disinfectants. Many experts suggested updates of the device design to make them easier to disinfect and clean. However, the panel unanimously agreed not to ban use of duodenoscopes as currently used since its benefits far outweighed the risks associated. Previously, FDA had issued a safety alert related to duodenoscopes in February, 2015. In that alert, FDA recommended “effective” reprocessing thorough step-by-step process to disinfect or sterilize these devices. The advisory panel recommended that patients be informed of the risk of infection with use of duodenoscope. This is not an isolated incidence of risk of reprocessed devices and it sure won’t be the last one. Stay tuned.

Article Source: Need to innovate the design of duodenoscope to enable infection free reprocessing

Blue Bell listeria outbreak exposes limitation of FDA’s food
inspection program

FDAMap Expert Opinion

Food facilities are not expected to report to FDA incidences of contamination unless they suspect that the contaminated food has entered distribution. Hence most food contamination found during manufacture are not reported to the FDA. Recent outbreak of listeria contamination at Blue Bells plants exposed this gap between expectation from and the reality of enforcement by FDA. FDA officials were never told about the numerous listeria and other contamination at the Blue Bell Creameries manufacturing facility. Only once there was a major outbreak, did the company made the news public and informed FDA. FDA investigation found this to be an ongoing problem at the facility. This is not the first time, FDA was the last to know of such incidences; In the last year, there have been 14 other such outbreaks. FDA is aware of these limitations in the law. The final version of the Food Safety rules, expected later this year will attempt to close this loophole and force companies to be more transparent regarding incidences of contamination and give FDA more authority to audit food manufacturing facilities. Food facilities should be ready to get audited by FDA and demonstrate compliance with good manufacturing practices soon as it is certain that FDA inspections of food facilities will increase in the near future.

Article Source: 
FDA’s Outbreak Incidence page
The Washington Post

FDA wants to further regulate hand cleaners used in hospitals 

FDAMap Expert Opinion

FDA issued a proposed rule of 1 May 2015 to revise a previous law from 20 years ago regulating over-the-counter (OTC) antiseptic products intended for use by health care professionals in a hospital setting or other health care situations outside the hospital. Hand cleaners are generally recognized as safe and effective, however recent scientific data has cast doubts about the overall protection from infections offered by certain hand cleaners indicating that these cleaners may not be as effective as previously thought. Under the new rule, when final, manufacturers of antiseptic hand cleaners will be required to provide additional cell culture (in vitro) and animal (in vivo) data to support the safety and effectiveness of antiseptic active ingredients. These include in vitro data characterizing the ingredient's antimicrobial properties and in vivo clinical simulation studies showing that specified log reductions in the amount of certain bacteria are achieved using the ingredient. The proposed rule is open for public comments for 180 days which is till 28 Oct 2015. [Learn about how to meet FDA to ask for advice]

Article Source: 
FDA’s antiseptic products
The Washington Post

FDA increased GMP audits of generic drug facilities by 60%

FDAMap Expert Opinion

In a recently published report from the Office of the Inspector General (OIG), in the last 2 years, FDA has increased GMP inspections of generic drug manufactures by almost two-thirds. About 90% of these inspections were surveillance inspections in which FDA randomly inspected facilities for compliance with GMP. FDA focused its inspections on “high risk” sites and increased its audits of non-US locations. The US and non-US sites were equally likely to get audited with about 50-50 split between the US and non-US audits. Still FDA could not complete all pre-approval audits requested by the Office of Generic Drugs leading to delays in approval of new generic drugs. About half of FDA audits ended with major findings that either led the manufacturer to voluntarily take corrective actions or the manufacturer being classified unacceptable by FDA. In the coming year, FDA promised to conduct more GMP audits to cover maximum number of manufacturing sites. It also plans to further enforce the facility registration with FDA and the request manufacturers to submit additional documents prior to the GMP audits to facility a more thorough and quicker audit. [Learn about FDA’s GMP regulations; Learn about how to withstand an FDA audit; Learn how to do meetings with FDA to seek advice on compliance issues]

Article Source: 
OIG report
The Wall Street Journal