FDA Lawyers Blog

The European Medicines Agency ("EMA") has released their report giving detailed information regarding numbers of patients, sites and inspections with respect to pivotal clinical trials submitted in marketing authorization applications ("MAA") between January 2005 and December 2011.

As we noted in a previous blog there has been an increase in concern amongst regulators and the public about how well clinical trials are conducted from an ethical and scientific/organizational standpoint, and especially with regard to good clinical practice ("GCP") compliance. An applicant has to provide information in every MAA regarding the location, conduct and ethical standards applied in respect of the clinical trials conducted in third countries.

The report relates mainly to new applications (485), line extensions (95), and variations where new clinical trial information was provided (97). Generic applications are included as part of the new applications, but they generally do not add much to the number of patients, because these applications are mainly based on small bioequivalence trials, but they do provide information on the locations where these trials were conducted.

For some time now, there have been strident calls for the publishing of all clinical trial data. The pressure has arisen due to revelations that companies may have hidden crucial clinical data that might have shown that the drug being tested was not as efficacious or even as safe as they appeared from quoted trial results (see, for instance, a previous blog here). The campaign group AllTrials has brought together several people and groups (including for example David Tovey, editor The Cochrane Library; Ben Goldacre (book Bad Pharma); Carl Heneghan, Centre for Evidence-Based Medicine, University of Oxford) because, as they put it:

Around half of all clinical trials have not been published; some trials have not even been registered. If action is not taken urgently, information on what was done and what was found in trials could be lost forever, leading to bad treatment decisions, missed opportunities for good medicine, and trials being repeated unnecessarily.

Key publications like the British Medical Journal and research bodies such as the Medical Research Council and the Wellcome Trust agree, the trust encouraging its grant recipients to release their trial data.

The European Medicines Agency ("EMA") has been looking at this for some time, with the same aim in mind and is trying to develop a workable policy to enable the data to be published. Indeed it is thought that in the next few weeks, major players in the United Kingdom's medical community will meet to try and take things further in a more practical manner.

On February 5, 2013, FDA announced the availability of Draft Guidance relating to the development of drugs for the treatment of early stage Alzheimer's disease. The Draft Guidance, titled, "Alzheimer's Disease: Developing Drugs for the Treatment of Early Stage Disease" addresses: (1) diagnostic criteria for early stage Alzheimer's disease; (2) appropriate clinical outcome measures; and (3) ways to demonstrate disease modification. Addressing these issues in early stage Alzheimer's disease poses unique difficulties, because patients may have little to no impairment of global functioning. FDA is seeking public comment on the Draft Guidance within sixty days.

The Draft Guidance provides FDA's current thinking on useful diagnostic criteria for early Alzheimer's disease. FDA cited useful research in developing diagnostic criteria, such as the research criteria for prodromal Alzheimer's disease and preclinical Alzheimer's disease. Specifically, FDA also cited as useful efforts by the research community to incorporate biomarkers into the diagnostic criteria. FDA concluded that, "we support the concept of enriching trial populations with patients most likely to progress to more overt dementia, using both clinical biomarker-based criteria." FDA also indicated, however, that FDA could not formally endorse any specific diagnostic framework, because more work was necessary to assess the specificity and sensitivity of these criteria, as well as the validation of these methodologies.

The Draft Guidance also provides FDA's current thinking on ways to establish clinical efficacy in trials involving patients suffering from early stage Alzheimer's disease. While FDA requires a co-primary outcome measure to demonstrate efficacy on both cognitive and functional levels for clinical trials on the dementia stage of Alzheimer's disease, in the draft guidance, FDA acknowledged that these endpoints may be impractical for patients suffering from early stage disease. Therefore, FDA indicated that for early stage disease "clear evidence of an effect on delaying cognitive impairment may provide sufficient evidence of effectiveness."

Earlier this week, the U.S. Supreme Court denied GlaxoSmithKline's certiorari petition in a case that would have helped clarify the scope of 35 U.S.C. § 271(e)'s safe-harbor provision. The issue facing the Court was whether section 271(e)(1) applies to postmarketing activity as well as premarketing activity.

Section 271(e), which states that it is not an act of infringement to make, use, offer to sell, or sell a patented invention "solely for uses reasonably related to the development and submission of information under [federal drug laws]," does not include a time limitation. The question about timing was highlighted in two recent Federal Circuit cases. In Classen Immunotherapies, Inc. v. Biogen Idec, 659 F.3d 1057 (Fed. Cir. 2011), the Federal Circuit explained that "§ 271(e)(1) is directed to premarketing approval of generic counterparts before patent expiration." Last year, however, a different panel of judges in Momenta Pharmaceuticals, Inc. v. Amphastar Pharmaceuticals, Inc., 686 F.3d 1348 (Fed. Cir. 2012) held that post-approval studies performed for the FDA fall within § 271(e)(1)'s safe harbor and explained that Classen held that 271(e)(1) "does not apply to information that may be routinely reported to the FDA, long after marketing approval has been obtained."

As previously blogged on here, the Solicitor General had urged the Supreme Court to deny GSK's petition in the Classen case. Despite a belief that the Federal Circuit erred in Classen, United States Solicitor General Donald Verrilli offered the following reasons why the Supreme Court should deny certiorari: (1) the Federal Circuit's Momenta decision sufficiently clarified and narrowed the Classen holding; (2) it was unclear whether the safe harbor applied to the types of patents at issue in the Classen case; and (3) the petitioners were not entitled to the safe harbor protection regardless of the Supreme Court's interpretation of the provision.

This Monday, the U.S. Supreme Court announced that it will not review a challenge to federal funding of human embryonic stem-cell research. By rejecting the petition from a pair of scientists opposing such funding, the Court gave the green light for controversial embryo-based studies to move forward.

Scientists James L. Sherley and Theresa Deisher sued the United States Department of Health and Human Services ("HHS") and the National Institutes of Health ("NIH") in 2009, challenging NIH guidelines related to human-stem cell research promulgated pursuant to Executive Order 13,505. E.O. 13,505 was signed by President Barack Obama in March 2009 with the aim "to expand NIH support for the exploration of human stem cell research." The order loosened limitations imposed by the previous administration on the use of federal tax dollars for embryonic stem cell research and overturned an order barring NIH from conducting research on embryonic stem cells beyond the 60 cell lines then in existence. In addition, it directed NIH to review its guidelines regarding stem-cell research.

Sherley and Deisher-both adult stem-cell researchers who do not conduct research on human embryos or embryonic stem cells-challenged the Guidelines on the grounds that: (1) NIH refused to address comments submitted in response to the draft version, in violation of the Administrative Procedure Act and (2) they violate the Dickey-Wicker Amendment. The Dickey-Wicker Amendment is an appropriations rider, included in every HHS appropriations bill since 1996, prohibiting the use of federal funds for "the creation of human embryo or embryos for research purposes" and "research in which human embryo or embryos are destroyed, discarded, or knowingly subjected to risk of injury or death greater than that allowed for research on fetuses in utero under [other federal regulations]." The final NIH Guidelines, published on July 7, 2009, authorized federal funding of research using live human embryos that were created "for reproductive purposes" (i.e., in vitro fertilization) but are "no longer needed for [that] purpose."

Towards the end of last year, FDA added two new final guidances related to the safety reporting requirements for investigational new drug exemptions ("INDs") and bioavailability and bioequivalence ("BA/BE") studies entitled: Guidance for Industry and Investigators: Safety Reporting Requirements for INDs and BA/BE Studies and Guidance for Industry and Investigators: Safety Reporting Requirements for INDs and BA/BE Studies-Small Entity Compliance Guide. These guidances are intended to explain final rules published on September 29, 2010 that amended the IND safety reporting requirements under 21 C.F.R. Part 312 and added safety reporting requirements for individuals conducting BA/BE studies under 21 C.F.R. Part 320. We blogged on that development then.

A key focus of the new regulations was to add clarifying definitions to certain terms, "adverse event", "suspected adverse reaction", "unexpected" adverse event or reaction, "serious" adverse event or reaction, and "life-threatening", as well as further define reporting requirements. According to the main Guidance (not the one for small entities), sponsors frequently took a broad reading of the phrase "associated with the use of the drug" in the context of the former 21 C.F.R. § 312.32(a), which stated, "there is a reasonable possibility that the experience may have been caused by the drug." With this broad reading, the Guidance continues, "sponsors frequently reported, as individual cases, serious adverse experiences for which there was little reason to believe that the drug caused the event." The Guidance includes three examples of overzealous reporting, including reporting adverse experiences that were manifestations of the underlying disease, common occurrences in the study population independent of drug exposure, or study endpoints. FDA described these types of reporting as a drain on agency resources and "uninformative when reported as single events (i.e., without a comparison of the incidence of the event in treated and untreated subjects), they do not contribute meaningfully to the developing safety profile of an investigational drug or to human subject protection."

Interestingly, this appears to be somewhat of a departure from how FDA had enforced its reporting regulations on clinical investigators. Shortly after I first joined FDA in the 1990s, I was involved in a clinical investigator disqualification proceeding that resulted in a clinical investor being disqualified from further clinical studies because, among other things, he had not timely or accurately reported certain adverse events. While the Presiding Officer took into account that many of the patients had underlying conditions prior to the experimental therapy, the Center for Drug Evaluation and Research ("CDER's") approach appeared to focus on the need for the investigator to report all adverse event associated with the therapy. In this case, the therapy had to do with infusing a drug with a catheter to help dissolve gall bladder and common bile duct stones, which the CDER described as a drug/device. The investigator admitted that he had not immediately reported certain events that occurred as a result of the catheter insertion (most likely not due to the drug) or the patient's underlying conditions, because in his opinion, they were not associated with the drug therapy. At that time, CDER took the approach that the investigator's opinion was irrelevant, because the adverse events were at least temporally associated with the drug/device and therefore had to be timely reported.

The Solicitor General has urged the U.S. Supreme Court to deny GlaxoSmithKline's ("GSK's") pending certiorari petition in GlaxoSmithKline v. Classen Immunotherapies, Inc., case number 11-1078 The issue facing the Supreme Court should it grant GSK's petition is whether the Federal Circuit correctly interpreted 35 U.S.C. § 271(e)(1)'s safe harbor as applying to only pre-market approval of generic counterparts. In its amicus brief submitted late last week, the Solicitor General explained that there is no need to clarify the safe harbor provision and voiced concerns that the Classen case would not be the proper vehicle to do so should the Supreme Court feel the need.

The dispute between GSK and Classen involves three patents, U.S. Patent Nos. 6,638,739, 6,420,139, and 5,723,283, which relate to methods of optimizing vaccine immunization schedules to decrease the risk of developing chronic immune-mediated disorders. Classen sued a number of defendants, including GSK, alleging infringement of its patents through various vaccination research projects. GSK's allegedly infringing activities related to its participation in a government study that evaluated a suggested association between the timing of childhood vaccinations and the risk of developing type 1 diabetes. GSK argued, and the district court agreed, that such activity was within section 271(e)(1)'s safe harbor because the information was ultimately submitted to FDA. On appeal, the Federal Circuit reversed, holding that section 271(e)(1) "does not apply to information that may be routinely reported to the FDA, long after marketing approval has been obtained." Classen Immunotherapies, Inc. v. Biogen Idec at 1070. The Federal Circuit further explained, "§ 271(e)(1) is directed to premarketing approval of generic counterparts before patent expiration." Id. at 1071.

In the amicus brief, United States Solicitor General Donald Verrilli expressed his belief that the Federal Circuit's interpretation of § 271(e)(1) in Classen was incorrect. 35 U.S.C. 271(e)(1) reads:

It shall not be an act of infringement to make, use, offer to sell, or sell within the United States or import into the United States a patented invention . . . solely for uses reasonably related to the development and submission of information under a Federal law which regulates the manufacture, use, or sale of drugs or veterinary biological products.

On November 19, 2012, FDA issued a draft Guidance entitled, "Electronic Source Data in Clinical Investigations." The Guidance recommends various procedures relating to the electronic capture of source data in clinical investigations in an effort to reduce errors, to provide real-time data access, and to maintain accurate records for inspection by study investigators and FDA.

Clinical Data Guidance

Source data includes all information found in original clinical investigation documents (or certified copies of original documents) and this information is used for the reconstruction and evaluation of clinical trials. Accurate transcription of source data is extremely important, and the Guidance discusses methods of identifying source data, creating easy identification methods for auditing, capturing source data, and reviewing and retaining the data. The Guidance discusses the identification of source data originators, the capture of source data, the creation of data element identifiers, and the investigator's duty to review and retain electronic data.

The Guidance focuses on data entered into electronic case report forms ("eCRFs"). An eCRF is an electronic record, created for all clinical study subjects, that is reported to the study sponsor as per the study protocol. eCRFs contain data elements that are entered into the system by data originators such as investigators, medical devices, and clinical investigation subjects. Data elements are the smallest units of observation made during a clinical investigation and they include observations such as weight, birth date, race, or body temperature. The Guidance recommends that each sponsor and investigator maintain a list of data originators (e.g., people and devices) authorized to enter data elements for each study protocol. These lists limit access to data entry by creating unique user names, passwords, and identifications and by setting time periods for when each data originator can enter data.

On September 19, ten top U.S. and European drugmakers announced that they have formed a new nonprofit organization called TransCelerate BioPharma Inc. ("TransCelerate") to help improve how experimental drugs are tested to get them to patients sooner. The New York Times broke the story, along with the Associated Press and Reuters getting the word out for this organization that has been in the works for about a year.

The ten companies are: (1) Abbott Laboratories Inc., (2) AstraZeneca Plc, (3) Boehringer Ingelheim, (4) Bristol-Myers Squibb Co., (5) Eli Lilly and Co., (6) GlaxoSmithKline Plc, (7) Johnson & Johnson, (8) Pfizer Inc., (9) Roche Holding's AG Genentech, and (10) Sanofi SA. TransCelerate's headquarters will be in Philadelphia, Pennsylvania, which it hopes to open later this year. All of the companies will contribute financial and other resources but for right now scientists and other staff are working from their corporate offices.

FDA's Director for the Center for Drug Evaluation and Research ("CDER"), Janet Woodcock, M.D., supported the move, said in a statement,

We applaud the companies in TransCelerate BioPharma for joining forces to address a series of longstanding challenges in new drug development.... This collaborative approach in the pre-competitive arena ... has the promise to lead to new paradigms and cost savings in drug development, all of which would strengthen the industry and its ability to develop innovative and much-needed therapies for patients.

The interim chief of the effort is Garry Neil, former Corporate Vice President for Science and Technology at Johnson& Johnson. "There's never been anything like this to take on these big challenges," Neil said, who has so far offered no details on how big this project will get other than the initial focus would be five projects to make clinical trials more efficient with a budget in the millions of dollars. "We want to simplify, standardize, and also raise quality. ... We worry about potentially promising drugs which might not get studies unless we can increase the overall efficiency of the system. I think it will make it easier for companies," Neil added.

On August 2, four members of the House of Representatives, led by Congressman Edward Markey, introduced, H.R. 6272, "The Trial and Experimental Studies Transparency (TEST) Act of 2012." The TEST Act will amend Section 402(j) of the Public Health Service Act, tightening the reporting requirements for the Internet site designed to better inform the public about ongoing and completed clinical trials in the United States, ClinicalTrials.gov. The main goal of the TEST Act is to prevent clinical-trial sponsors from withholding negative study data and safety concerns while emphasizing the positive results of their clinical trials.

Prior to the proposed TEST Act, under the Food and Drug Administration Amendments Act of 2007 ("FDAAA"), most United States-conducted interventional clinical trials were registered at ClinicalTrials.gov, and most of the results of those clinical studies were eventually published. However, loopholes in the requirements of the FDAAA resulted in clinical studies that were either not registered, that failed to report results, or both. There are a number of clinical trials, therefore, that are not registered in the publically-accessible database.

The TEST Act will require all interventional biomedical studies conducted on humans to be registered on ClinicalTrials.gov prior to enrolling any patients. In addition, sponsors of these clinical trials will be required to post the study results and other required information on ClinicalTrials.gov within one year of the completion date of the trial. According to the proposed legislation, interventional studies include all human studies where patients are assigned, via protocol, by an investigator to receive specific intervention where the effects of such intervention on biomedical or health-related outcomes are evaluated. For clinical trials involving drugs or medical devices that have never been approved for any use, the TEST Act permits a delayed results submission of up to two years from the date of completion of the clinical trial.

There has been an increased effort to increase pediatric testing for adult medications, due to the expense of pediatric clinical trials and parent concerns about participation. For example, an alarming 70 percent of medications prescribed for children have never been tested on them, the National Institute of Health ("NIH") estimates.

In an effort to address the issue, on July 9, 2012, President Barack Obama reauthorized the "Best Pharmaceuticals for Children Act" and "Pediatric Research Equity Act" providing drug companies with a six month period of "pediatric exclusivity" if they perform studies approved by the FDA. This approval is a main proponent in easing parents' minds when allowing their own children to participate in clinical trials. In addition, such initiatives have helped incentivize sponsors to conduct more pediatric research with NIH funding for pediatric research rising by 18% "from $2.77 billion in 2008 to $3.28 billion in 2011.

Still, while improvements are on the horizon, there is much to be done to fully address the lack of pediatric clinical trials. A July 23 study in Pediatrics found a scarcity in pediatric drug trials as well. Dr. Florence T. Bourgeois, lead researcher on the new study, expressed concern that doctors have long been known to "extrapolate" findings from adult studies to then apply them to children. Bourgeois said that "children are not small adults." Due to children's developing bodies, they metabolize drugs differently than adults do. In fact, children encounter disease just as frequently, or more so, than adults, according to Bourgeois, yet "[c]hildren continue to be underrepresented in clinical trials compared with their burden of disease." Overall, just 12 percent of all clinical trials focused on children and teenagers. Yet children accounted for 60 percent of those suffering the conditions studied. Bourgeois said that more may need to be done to encourage not only drug company trials, but studies funded by non-commercial sources as well.

"One of FDA's top priorities is giving pediatricians and parents the same level of tested and researched information on drugs used to treat children that is required for drugs used to treat adults," FDA spokesperson Sandy Walsh reportedly said. "Congress has helped increase studies for children by passing legislation that gives companies financial incentives to conduct pediatric studies and to require them to study a product they are developing for adults if the disease also occurs in children," Walsh added.

The impact and influence of the Best Pharmaceuticals for Children Act and Pediatric Research Equity Act will be discussed by FDA's Pediatric Advisory Committee this upcoming September. The meeting agenda includes the discussion of pediatric-focused safety reviews as mandated by both of the recently authorized Acts.

On July 17, 2012, FLH Partner Brian J. Malkin joined other experts in the field of clinical trials to discuss methods for ensuring safe and compliant domestic and international clinical trials. New to the ACI's Clinical Trials Conference running for more than seven years was Malkin's presentation "Safely Conducting Biosimilars Clinical Trials: Understanding FDA's Requirements for Biosimilar Clinical Trials". The audience was comprised of many individuals seasoned in traditional clinical trials, who came to the conference in Boston to learn about the newest trends in clinical trials.

Some of the featured government speakers included Karena Cooper, J.S., M.S.W., Acting Associate Director of Policy and Communications and Regulatory Counsel, Office of Scientific Investigations ("OSI"), Center for Drug Evaluation and Research, FDA, and Mary E. Crawley, Assistant U.S. Attorney, Eastern District of Pennsylvania. Other featured speakers included former government enforcers and top in-house counsel from sponsor biopharmaceutical and medical device companies, contract research organizations ("CROs"), hospitals, universities, and research institutions.

Cooper described FDA's new inspection platform, where FDA does not need to inspect a facility to issue a warning letter, and the reorganization of the Office of Compliance. In terms of postmarket studies, sponsors are now provided with milestone timetables where failure to complete a milestone by a certain time will result in a violation. While a sponsor may show "good cause" for failure to meet a milestone, FDA has a very limited high bar, essentially for items completely outside the sponsor's control. Examples where FDA did not find good cause included difficult recruitment, costly studies, or development of data in lieu of the data that the sponsor agreed to provide. Regarding postmarket studies, however, FDA has already issued its first warning letter dated February 17, 2012 that utilized the no-inspection format. In this letter, FDA provided the sponsor with 30 calendar days to respond. FDA's Office of Compliance also has new civil money penalties to enforce its provisions that Cooper said FDA is "actively considering" but has not utilized yet. Cooper also described how FDA is working with the European Medicines Agency ("EMA") for joint and observed inspections, where there is a "robust" confidentiality agreement in place.

The promise of gene therapy as a commercially-available tool for treating genetic disorders may finally be inching closer to reality. On July 20, 2012 the European Medicines Agency ("EMA") Committee for Medicinal Products for Human Use ("CHMP") took the first step towards making gene therapy treatment a reality by recommending the gene therapy, Glybera® (alipogene tiparvovec), for marketing approval in the European Union ("EU"). Glybera®, which is indicated for the treatment of lipoprotein lipase ("LPL") deficiency, was developed by Netherlands-based, uniQure.

Patients lacking LPL enzymes are unable to break down fats. The CHMP press release states that:

So far, management of patients with the disorder consists of strict reduction of dietary fat to less than 20% of the daily caloric intake. It is very difficult to comply with such a dietary regimen and as a consequence many patients experience life-threatening pancreatitis attacks requiring admission to hospital.

Due to the difficult circumstances faced by individuals suffering from LPL deficiencies that trigger severe or multiple pancreatitis attacks, the CHMP has deemed the treatment benefits afforded by this gene therapy to be worth its risks.

Fundamentally, gene therapy is a method by which exogenous "functioning" or "normal" DNA replaces "abnormal" DNA that is responsible for a particular genetic disorder. Gene therapy was originally touted in the 1970s as a potential way to treat genetic disorders.

Frommer Lawrence & Haug LLP Partner Brian J. Malkin will present a controversial topic concerning the type of clinical trials that FDA will require for biosimilar product applications entitled: "Safely Conducting Biosimilars Clinical Trials: Understanding FDA's Requirements for Biosimilar Clinical Trials". Mr. Malkin will address what FDA has said about its "selective and targeted approach" for biosimilar clinical trials and how biosimilar applicants may be able to rely on certain clinical trial data from the innovator's product, as well as assessing the risks and benefits for conducting such clinical trials. Mr. Malkin's presentation is part of the American Conference Institute's 14th Advanced Summit on Clinical Trials: Ensuring Safe and Compliant Domestic and International Clinical Trials on July 17-18, 2012 in Boston.

On July 17, Frommer Lawrence & Haug LLP Partner Brian Malkin will speak on a tough, new topic concerning what type of clinical trials FDA will require for supporting marketing applications for biosimilar products entitled: "Safely Conducting Biosimilars Clinical Trials: Understanding FDA's Requirements for Biosimilar Clinical Trials". Topics that Mr. Malkin will cover include understanding FDA's "selective and targeted approach" for biosimilar clinical trials, relying on clinical trial data from the innovator's product, and assessing the risks and benefits for conducting such clinical trials. Mr. Malkin's presentation will be part of the American Conference Institute's 14th Advanced Summit on Clinical Trials: Ensuring Safe and Compliant Domestic and International Clinical Trials on July 17-18, 2012 in Boston.

ACI Clinical Trials 2012