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India is planning to add the European Union to the list of regions covered by its clinical trial waiver rule. The change will free companies from the need to run clinical trials of medical devices that are already available in the EU when they want to access the Indian market.

In the Medical Device Rules, 2017, Indian legislators agreed to waive the need for clinical trials when a device is “approved by the regulatory authorities of either the United Kingdom or the United States of America or Australia or Canada or Japan and the said device has been marketed for at least two years in that country.” The EU is the notable omission from that list.

Representatives of the EU pointed out the omission at a meeting of the India-EU subcommission on trade in 2018, leading to the matter being referred to the Drugs Technical Advisory Board (DTAB). In meeting minutes published this week, DTAB agreed to change the rules to include the EU.

The change was one of a clutch of recommendations made by DTAB at the meeting. DTAB also looked at good distribution practices (GDPs), a subject it has considered several times in the past. The focus on GDPs reflects a concern that the current Indian rules enable unauthorized entities to distribute and sell medicines, leading to the introduction of spurious drugs into the legal supply chain.

Faced with that problem, DTAB thinks Indian legislators should make provisions for GDPs in the Drugs and Cosmetics Rules, 1945. The recommendation follows a request for feedback on draft GDP guidelines.

The fallout from the N-Nitrosodiethylamine (NDEA) and N-Nitrosodimethylamine (NDMA) impurities fiasco continues as the US Food and Drug Administration (FDA) last week sent a warning letter to India-based Lantech Pharmaceuticals.

Lantech, which was placed on import alert in June and acts as a contract solvent recovery facility for valsartan active pharmaceutical ingredient (API) manufacturers, failed to perform an adequate investigation into a customer’s contaminated valsartan API, FDA said.

Although the investigation focused on NDEA, FDA said Lantech also failed to investigate NDMA samples collected from its equipment. In addition, the Lantech investigation failed to include non-dedicated storage, receiving and charging tanks used in its solvent recovery operations, FDA said.

And although Lantech manufactures angiotensin II receptor blockers (ARBs) including valsartan, telmisartan and olmesartan API and intermediates for countries outside the US, the firm failed to adequately evaluate the potential of these ARBs to form nitrosamines and potentially cross contaminate drugs shipped into the US.

“In your response, you stated that you were unaware of specific aspects of your customer’s valsartan API manufacturing process which were important for predicting nitrosamine formation in the solvent recovery process. Your response is inadequate because it is your responsibility to understand all the potential risks associated with the drug manufacturing processes conducted at your facility,” the warning letter says.

FDA investigators also found “solid and liquid material of unknown origin…pooling at the bottom of a non-dedicated receiving tank.” And FDA said that the company “admitted to routinely deleting recovered solvents gas chromatography (GC) data older than three months permanently, without any backup.”

But this is not the first NDEA- or NMEA-related warning letter, as the agency also sent a warning letter to Indian manufacturer Aurobindo last month, saying the firm failed to adequately investigate the root cause of impurities. China-based Zhejiang Huahai Pharmaceuticals also drew a warning letter last December over failures to conduct investigations into the impurities.

Emtech Pharmaceuticals

In addition to the Lantech warning letter, FDA on Tuesday also released a warning letter for India-based Emtech Pharmaceuticals, which was found to have repeat observations from a previous FDA inspection in 2017.

“FDA cited similar CGMP observations in which you inadequately performed microbiological investigations. Repeated failures demonstrate that executive management oversight and control over the manufacture of drugs is inadequate,” FDA said. The agency also noted that the firm’s sterility failure investigations lacked sufficient data to support its conclusions.

Lantech Pharmaceuticals Limited

Biomedical research is advancing rapidly and a key part its advancement is in the analytical capabilities allowing comparison between a reference biological product and a biosimilar product. In “Comparison of Data Requirements for the Approval of a Biosimilar Versus the Reference Medicine,” senior regulatory affairs consultant Olivia McBride defines both biologics and biosimilars and explains how and why the two differ in terms of their organic natures. She also guides the reader through the biologic vs. biosimilar developmental and testing stages and through agency approval and postmarketing surveillance.

As the cost to bring therapies to market is ever increasing and demand for better, more targeted drugs and vaccines continues to grow, new technology has become a major driver to expand the development pipeline and get products to patients faster. In “Transforming Regulatory Operations,” GSK executives Eckart Schwarz and Adrian Cottrell make the business case for reorganizing its regulatory operations function, centralizing regulatory processes and implementing cloud-based technology to modernize regulatory information management. The authors describe the journey toward productive change in an effort to improve efficiencies, maintain compliance with new standards and gain greater internal alignment.

Changing Global Regulatory Landscape

The Chinese regulatory system for marketing authorization differs from other regulatory systems, especially with regard to inspection and analytical testing requirements. As part of the Marketing Authorization (MA) procedure for pharmaceutical products in China, the Chinese National Medical Products Administration (NMPA) normally requires a manufacturing site inspection to be performed and for analytical test methods to be validated, prior to granting an MA. Regualtory expertYingying Liu summarizes new guidance released by the Chinese Drug Evaluation (CDE) Agency in “China NMPA Publishes new Notification on Regulatory Inspection and Analytical Testing Documentation.”

India’s Ministry of Health and Family Welfare (MoHFW) has published the final version of New Drugs and Clinical Trials Rules, 2019. In “India’s New Drugs and Clinical Trials Rules: An Industry Perspective,” Parveen Jain and Rahul Chauhan explain the new regulatory pathway, including the changes and their impact on industry and clinical trials. The experts cover product registration, changes to clinical trials rules, revisions to “new drug” definitions, postmarketing studies, orphan drug registration, ethics committees, fees and waivers and the importation and manufacture of unapproved new drugs.

Requirements for cleanrooms are among the most critical issues of Good Manufacturing Practices (GMPs), but differences between requirements in the US and EU could cause confusion and misunderstandings that could pose safety risks. GMP expert Aleksandr Fedotov discusses the contradictions between the US and EU requirements for cleanroom GMPs in “FDA and EU GMP Annex 1 Differences in Cleanroom Specifications” and specifies particle concentration for cleanrooms “at rest,” particle contamination in the air, start-up testing vs. routine monitoring, risk analysis and “interlocking” doors. He suggests the need for a globally harmonized GMP for cleanroom operation based on practical experience and scientific evidence.

There are several reasons for a company’s pursuit of accelerated development pathways for a new drug or biologic. Regulatory expert Bridget Heelan presents several reasons and summarizes accelerated pathways for regulatory approval for new drug or biologic development in the European Union (EU) in “EU Accelerated Pathways.” She presents requirements for conditional marketing authorization, authorization under exceptional circumstances, accelerated assessment and Priority Medicines Scheme (PRIME) in addition to accelerated pathway requirements associated with orphan drug designation.

Global Regulatory Strategy

The introduction of the internet in 1989 and the subsequent connection of critical medical systems in the late 1990s has improved the quality and efficiency of healthcare. However, this connectivity introduced additional risks to patient care and privacy. In “Medical Device Cybersecurity Regulatory Pathway,” medical device expert Carolyn Wright discusses the changes in technology and the need for cybersecurity, recent developments in cybersecurity regulatory and postmarketing requirements and cybersecurity risk management programs. In addition to presenting regulatory history, she includes some best practices for medical device product development teams who are looking to design in cybersecurity.

Jehangir Hospital, along with its research arm Jehangir Clinical Development Centre (JCDC), is bringing its patients access to international clinical trials by joining Clinerion’s Patient Network Explorer platform. JCDC is the research arm of Jehangir Hospital, Pune, India. The hospital has over 350 beds, servicing patients throughout Pune and beyond. It has a wide range of disease-area specializations, including, but not limited to: cardiology, oncology, endocrinology, pediatrics, rheumatology, dermatology and infectious diseases. JCDC has over 60 principal investigators and conducts on average 25-30 clinical studies at any point of time.

Clinerion’s Patient Network Explorer helps partner hospitals be visible to pharmaceutical companies seeking suitable patients and sites for their clinical trials. Queries based on trial protocols may be sent to partners to assess the count of eligible patients in their electronic health records. All patient data is de-identified and remains under the control of the hospital and inside its IT infrastructure. However, Clinerion’s patented technology also enables authorized trial staff at the hospital to re-identify the patient for the purpose of trial recruitment.

“We at JCDC are delighted about partnering with Clinerion as there is an ideal alignment of Clinerion’s innovative technology and our clinical research expertise,” says Pathik Divate, CEO of the JCDC. “We are excited about harnessing the power of this technology to leverage our diverse patient population and bring in further efficiency in patient recruitment.”

“The population of India is significantly under-represented when it comes to participation in clinical research. Patient Network Explorer can cut a path through the forest, leading sponsors to the institutions and clinicians who can support clinical trials at an international level of expertise and facilities. This collaboration with Jehangir is just the first step in enabling a global population of eligible patients which reflects the diversity of the world, itself,” says Ian Rentsch, CEO of Clinerion.

Celgene’s $7 billion bet on San Diego-based Impact Biomedicines is paying off. This morning, the U.S. Food and Drug Administration (FDA) approved Impact’s Inrebic (fedratinib) for the treatment for adult patients with certain types of myelofibrosis, cancers of the bone marrow.

The approval marks the second treatment for myelofibrosis. Incyte Corporation’s Jakafi (ruxolitinib), approved in 2011, was the first treatment in the U.S. for myelofibrosis. Richard Pazdur, director of the FDA’s Oncology Center of Excellence and acting director of the Office of Hematology and Oncology Products in the FDA’s Center for Drug Evaluation and Research, called the approval of Inrebic “another option for patients” with the rare bone marrow disorder. Pazdur said the FDA promotes the development of new treatment options for rare diseases “as not all patients respond in the same way.”

Inrebic is a highly selective JAK2 kinase inhibitor, for patients with treatment-naïve myelofibrosis, a bone marrow disorder that disrupts normal production of blood cells due to the development of scar tissue. As a result, the production of the blood cells moves from the marrow as to the spleen and liver, which causes enlargement of the organs.

Impact picked up fedratinib from Sanofi, which cast off the drug in 2013 after patients developed Wernicke’s encephalopathy, a neurologic emergency related to a deficiency in thiamine. Inrebic does include a Boxed Warning regarding the development of Wernicke’s, as well as other forms of encephalopathy. Serious encephalopathy was reported in 1.3% of patients treated with Inrebic in clinical trials, Celgene said. During clinical testing, the FDA placed a temporary hold on the development of Inrebic due to safety concerns, but it was later lifted and testing resumed.

Celgene Chief Medical Officer Jay Backstrom called the approval of Inrebic “another important milestone” for Celgene, which is in the midst of merging with Bristol-Myers Squibb. Backstrom said Inrebic is a new treatment option for myelofibrosis patients, including some who may have previously been treated with Jakafi but need a new option.

Inrebic was approved based on results of the late-stage JAKARTA trial that showed 35 of 96 patients treated with the fedratinib 400 mg daily dose experienced a significant therapeutic effect. As a result of treatment with Inrebic, 36 patients experienced greater than or equal to a 50% reduction in myelofibrosis-related symptoms, such as night sweats, itching, abdominal discomfort, feeling full sooner than normal, pain under ribs on left side, and bone or muscle pain, , the FDA said in its announcement.

The approval of Inrebic was granted under Priority Review. Inrebic also received Orphan Drug designation, which provides incentives to assist and encourage the development of drugs for rare diseases.

Although some of the top-selling drugs in the world are facing patent cliffs between now and then, many of them are still projected to continue being big sellers between now and 2024. A recent report by Evaluate Pharma estimates prescription drug sales will hit $1.18 trillion by 2024, driven by cell and gene therapies.

The report states, “The advances in cutting edge science are, for now, outpacing the traditional pricing and reimbursement systems the industry has been built on. This disconnect is leaving both patients and payers wondering how accessible these life-altering products will be.”

That said, many of the best-selling drugs in the world have been on the market since the late 1990s and are expected to continue strong sales.

Here’s a look at what Evaluate Pharma predicts will be the top-selling drugs from 2019 to 2024.

#1. Humira. AbbVie’s blockbuster drug for Crohn’s disease, rheumatoid arthritis, psoriatic arthritis, juvenile idiopathic arthritis, ulcerative colitis and ankylosing spondylitis is expected to rake in $103.95 billion from 2019 to 2024, despite looming biosimilar competition. AbbViebid to acquire Allergan for $63 billion in June. At least one of the reasons is to minimize its dependence on Humira.

#2. Lipitor. Yes, people still have high cholesterol, and Pfizer’s statin is still one of the best products to treat it. It is projected to bring in $15.76 billion from 2019 to 2024. Since its approval to 2018, the drug brought in $164.43 billion. It lost patent protection in 2011, causing sales to drop, but until recently it was considered the best-selling drug of all time.

#3. Enbrel. Approved by the U.S. Food and Drug Administration (FDA) in 1998 for rheumatoid arthritis, Amgen’s Enbrel is projected to rake in $31.66 billion from 2019 to 2024. The drug was originally developed by Immunex, which was acquired by Amgen in 2002. It has since picked up approvals for polyarticular juvenile idiopathic arthritis, psoriatic arthritis, ankylosing spondylitis, plaque psoriasis and pediatric plaque psoriasis.

#4. Rituxan. Genentech, a Roche company, received approval for Rituxan in 1997, a full 12 years before Roche acquired the biotech. Rituxan is approved for non-Hodgkin’s lymphoma, chronic lymphocytic leukemia, rheumatoid arthritis, microscopic polyangiitis, granulomatosis with polyangiitis and pemphigus vulgaris. It is projected to hit $24.57 billion in sales from 2019 to 2024. It created $111.5 billion in sales in the 19 years it has been on the market.

#5. Revlimid. Celgene’s Revlimid was approved in 2008 for multiple myeloma and has since been indicated for myelodysplastic syndromes and mantle cell lymphoma. Sales from 2019 to 2024 are projected to hit $69.95 billion. Sales from 2008 to 2018 were $53.69 billion. The patent expires in 2022. Bristol-Myers Squibb acquired Celgene for $74 billion this year.

#6. Remicade. Janssen Biotech, a Johnson & Johnson company, received approval for Remicade in 1998. It was initially approved for Crohn’s disease and has since been approved for a range of inflammatory disorders including rheumatoid arthritis, ankylosing spondylitis, psoriatic arthritis, ulcerative colitis, pediatric Crohn’s disease, plaque psoriasis and pediatric ulcerative colitis. It is projected to have sales of $19.2 billion between now and 2024. It has raked in $98 billion from 1998 to 2018.

#7. Epogen. Another Amgen drug, Epogen was approved in 1989 for anemia related to chronic renal failure. It has since been approved for breast, non-small cell lung, head and neck, lymphoid and cervical cancers. Sales from 2019 to 2024 are estimated to hit $7.97 billion. Total sales to date have totaled $107.9 billion.

#8. Herceptin. Developed by Genentech, Herceptin was approved in 1998 for overexpressing breast cancer. It was later approved for HER2-positive metastatic stomach cancer. From 1998 to 2018, it brought in $87.97 billion in sales and is projected to hit sales of $26.92 billion between 2019 and 2024.

#9. Avastin. Also a Genentech/Roche drug, Avastin was approved in 2004 for metastatic colorectal cancer, but has since been given the thumbs-up for breast, lung, glioblastoma multiforme, renal cell carcinoma, cervical, ovarian, Fallopian tube and peritoneal cancers. From 2004 to 2018 sales were $87.13 billion. It is projected to bring in $27.14 billion from 2019 to 2024.

#10. Advair. Developed by GlaxoSmithKline, Advair is used to treat asthma and chronic bronchitis. It was approved in 1998 and from then to 2018, brought in $104.2 billion. It is projected to sell $9.41 billion from 2019 to 2024.

Gene therapy companies could be continued M&A targets for larger ones as more and more companies are looking to broaden their therapeutic focus with potential one-time therapies for various diseases.

In a note to investors, Canaccord Genuity analyst Michelle Gilson, pointed to the M&A activity already occurring around AAV gene therapy platforms and anticipated that more activity will follow due to scarcity value.

“… for companies looking to make their initial investment into AAV gene therapy, acquiring a platform with initial proof-of-concept clinical data and manufacturing investments already in place seems to be essential–but increasingly expensive as these platforms command scarcity value,” Gilson said in her note.

Over the past couple of years several larger companies, such as Novartis and Roche, have dived into gene therapy with the acquisitions of companies such as AveXis and Spark Therapeutics. In May, Novartis’ AveXis won approval for its spinal muscular atrophy gene therapy Zolgensma. Novartis acquired AveXis last year for $8.7 billion. Earlier this year, Roche snapped up Spark for $4.8 billion. The deal provided Roche with Luxturna (voretigene neparvovec), a gene therapy for a rare, genetic form of blindness. Other AAV-associated acquisitions include Biogen’s $800 million deal for U.K.-based Nightstar Therapeutics, a company focused on ophthalmology gene therapies, and Ultragenyx’s 2017 acquisition of Dimension Therapeutics.

In analyzing the four big AAV-associated deals of the publicly-traded companies, Gilson said there were several hallmarks that each of the companies shared that made them such attractive M&A targets. Those four acquisitions were bolstered by “clear evidence of activity” in the clinic in at least one gene therapy program. Also of note, Gilson said the companies had made “major manufacturing investments” at the time of the acquisitions. Additionally, she said that pricing comps were clear for the lead programs. With those three common threads in mind, Gilson said for companies looking to make a move into the AAV area, there are “likely a limited number” of platforms that could make good near-term targets for pharma companies.

With those three benchmarks in mind, multiple gene therapy companies have been making similar internal moves, which could potentially put them on the radar for other companies. For example, in April, Audentes Therapeutics expanded its scientific platform and pipeline to advance vectorized antisense treatments for the treatment of Duchenne muscular dystrophy (DMD) and myotonic dystrophy type 1 (DM1). The company combines the delivery power of AAV with the precision tools of antisense oligonucleotides to develop potential best-in-class therapeutic candidates for these neuromuscular diseases.

Maryland-based REGENXBIO announced plans to build a new manufacturing facility to support future clinical and commercial production for its NAV technology-based AAV gene Therapies. The facility will be added on to the company’s 132,000 square foot headquarters, which is currently under construction. The new site is expected to be operational in 2021, the company announced in May. That new construction came ahead of the company announcing an expansion of its pipeline to include AAV-based therapies to include treatments for hereditary angioedema (HAE) and neurodegenerative diseases, including tauopathies, using NAV Vectors. Only days ago REGENXBIO and Pfizer announced a partnership to develop a gene therapy treatment for Friedreich’s ataxia, the most common hereditary ataxia.

Also in July, Philadelphia-based Passage Bio, which is developing AAV-delivered gene therapies for the treatment of rare monogenic central nervous system diseases, announced it entered into a collaboration agreement with Paragon Gene Therapy, a unit of Catalent Biologics, for the development of a dedicated manufacturing suite at their facility near Baltimore. The facility is expected to be operational in the second half of 2020.

As anyone following Alzheimer’s research knows, drug development for the disease has been a wasteland of failed clinical trials with literally billions of dollars thrown at drugs that have proved ineffective at preventing or halting the disease. In March 2019, in what many felt was a turning point for the industry, Cambridge, Massachusetts-based Biogen and its collaboration partner, Tokyo-based Eisai, announced they were discontinuing the global Phase III clinical trials, ENGAGE and EMERGE, of aducanumab in patients with mild cognitive impairment from Alzheimer’s and mild Alzheimer’s dementia. Biogen also discontinued its EVOLVE Phase II trial and the long-term extension PRIME Phase Ib trial of aducanumab.

Aducanumab was an antibody against beta-amyloid. Beta-amyloid is a protein that accumulates in the brains of Alzheimer’s patients and for the last several decades has been viewed as the primary cause of cognitive and memory issues caused by Alzheimer’s. Although most researchers believe beta-amyloid plays a role in Alzheimer’s, aducanumab was one of the final examples showing that preventing or eliminating beta-amyloid did not resolve the Alzheimer’s symptoms. Many critics said the amyloid theory of Alzheimer’s was officially dead.

It’s probably not dead, but it’s almost certainly being modified, and many researchers are shifting their attention and resources elsewhere.

UsAgainstAlzheimer’s is a nonprofit focused on stopping the disease. It recently published a research report providing an overview of the clinical trial pipeline for Alzheimer’s disease. George Vradenburg, chairman and co-founder of UsAgainstAlzheimer’s took time to speak with BioSpace about the report and current approaches to battling the disease.

“The report is basically demonstrating the pipeline continues to be fairly robust, but the number of Phase III trials, given the failures, is down appreciably and the number of Phase IIs is holding steady and increasing a bit,” Vradenburg said. “The Phase IIs are getting more diverse in terms of the methods of action and their targets. It is reflecting some move away from the amyloid hypothesis, although there are significant ongoing trials in the amyloid thesis.”

The report indicates there are currently 26 drugs in Phase III, a decrease of 16% since 2018. Nine of those drugs are focused on symptoms, while 17 are disease-modifying drugs. Six of the drugs are in prevention trials. Seven drugs are classified as targeting amyloid—down 30% from 2018—while 12 are classified as targeting neurotransmission.

Phase II, however, has 72 drugs, with 13 for symptoms, 59 targeting disease-modification, and only two in prevention trials. In what might be a larger shift, 12 drugs are focused on tau, another protein cluster implicated in Alzheimer’s, while five are classified as neuronal and synaptic growth, which is an increase of 67% from 2018.

“Tau is complicated,” Vradenburg said. “It presents in different parts of the brain and it is found in CTE (chronic traumatic encephalopathy) cases where there’s no amyloid engagement. There are obviously challenges in tau, but it’s later in the supposed amyloid-tau-neuroinflammation sequence, but not at the end. There’s a small group of evidence that suggests tau may start earlier or in parallel. The scientific community doesn’t have consensus on exactly what the sequence is.”

One striking aspect of the report is a table titled, “Alzheimer’s Drugs and Estimated Commercial Launch Dates.” Those launches, of course, are totally dependent upon the results of Phase II and particularly Phase III clinical trials. These mid- and late-stage trials are where Alzheimer’s drugs, historically, have gone to die, and in its own way the table is a show of optimism.

“If we look at the history of the last 15 years,” Vradenburg told BioSpace, “none of them are going anywhere, but you have to maintain hope, optimism and persistence. Seven million people probably die a year around the world each year of Alzheimer’s, 10 million get dementia related to this disease. We’ve got to keep at it with passion, pace and resources. Probably a lot will go nowhere, but we’ll see.”

Vradenburg also spoke about other approaches UsAgainstAlzheimer’s is taking and concerns the organization and many in the Alzheimer’s community have about drug development and treatments in this area.

“The marketplace isn’t ready,” Vradenburg notes.

Almost all of the drugs target the early stages of the disease, he said. And because the disease is complex, many believe that an effective medical approach will require combinations of drugs, not unlike what is being done in the HIV/AIDS arena, or likely to occur in nonalcoholic steatohepatitis (NASH), where multiple drugs will be needed to handle different components of the disease. Since there are few if any really effective Alzheimer’s drugs now, a combination approach would require not just one new and effective drug, but one after the other.

“There’s a real sense amyloid is still a player in some fashion,” Vradenburg said. “APOE4 is based on an amyloid precursor protein, so it’s a player, but whether we’ve got the wrong drug hitting the right target at the wrong time or whether we are not going early enough in the course of the disease to hit at the right time, are all factors.”

In addition, there are simply concerns about access, assuming a drug or multiple drugs are developed and approved. “Most of the people I’ve talked to in this space,” Vradenburg said, “are now focused on the fact that there’s a lot more to getting a successful drug into the hands of millions of people, or into the mouths of millions of people, beyond understanding the science.”

You need, he points out, to not only understand the basic science and develop drugs that interrupt the pathophysiology of the drugs so it affects the course of the disease, you have to have regulators willing to verify the therapies are safe and effective, and that the people who are paying for the drug will do so.

Which can be something of a conundrum, because although there are now no effective clinical diagnostic tests for Alzheimer’s, many of the drugs being evaluated are targeting earlier and earlier in the disease—without biopharmaceutical companies being 100% certain that the patients actually have Alzheimer’s.

Biomarkers and diagnostic tests for the disease have risen to the top of concerns in the industry, and specific efforts are focused on it. In April, for example, Bill Gates, Jeff Bezos and MacKenzie Bezos teamed up to donate more than $20 million to the Diagnostics Accelerator, a project part of the Alzheimer’s Drug Discovery Foundation (ADDF). The accelerator’s mission is to develop an easy and affordable test for Alzheimer’s disease.

UsAgainstAlzheimer’s is also planning a research report on the biomarker pipeline for Alzheimer’s.

Without good biomarkers, it’s going to be a difficult battle to convince payers like Medicare or insurance companies to pay for long-term therapies that may be very expensive, without clear diagnoses and prognostic assays to determine if the patient actually needs the drugs or if they’re effective.

Vradenburg is optimistic. “It’s a whole series of interrelated, logically sequential steps, each of which has to be identified and addressed. I think we’re getting things lined up.”

UsAgainstAlzheimer’s has created its own clinical trial enabling system called the Global Alzheimer’s Platform, which is working to speed the delivery of drugs by decreasing the time and cost of Alzheimer’s clinical trials. They are also working with regulators globally to acknowledge that Alzheimer’s drugs do not require both improvements in cognition and function in order to be approved, because researchers are working in populations where there are no cognitive deficits—meaning there’s nothing to improve, at least clinically. And as such, biomarkers are going to be increasingly important for clinical trial approvals.

UsAgainstAlzheimer’s also has a focus on research on lifestyle interventions—aerobic exercise, diet, and other activities that have been shown to have a positive action on preventing or slowing the disease.

“We’ll keep at this,” Vradenburg said. “But it’s a devil of a problem and a devil of a disease.”

In May, the U.S. Food and Drug Administration (FDA) approved Novartis’ gene therapy Zolgensma as a one-time treatment for spinal muscular atrophy. On Monday though, the regulatory agency revealed that data manipulation was involved in the preclinical process but suggests that the therapy remain on the market.

In an announcement Monday, the FDA said on June 28, more than a month after the agency approved the gene therapy, AveXis Inc., a Novartis subsidiary, informed the FDA “about a data manipulation issue that impacts the accuracy of certain data from product testing performed in animals submitted in the biologics license application.” The FDA said it is carefully assessing the information and situation, but “remains confident” that Zolgensma should remain on the market.

The FDA said its concerns are “limited to only a small portion of the product testing data that was contained in the marketing application.” That testing data was used by AveXis to support the development of its production process, the FDA said, but added that the data does not change the agency’s positive assessment of the information from the human clinical trials that were conducted as part of the development program.

“The totality of the evidence demonstrating the product’s effectiveness and its safety profile continues to provide compelling evidence supporting an overall favorable benefit-risk profile. However, the integrity of the product testing data used in the development of the product’s manufacturing process is still a matter that we are continuing to evaluate and take very seriously,” the FDA announced Monday.

In a statement issued Tuesday, Novartis said it stands behind the Zolgensma data. Novartis said the assays in question were used for initial product testing and are not currently used for commercial product release.

“We maintain that the totality of the evidence demonstrating the product’s effectiveness and its safety profile continue to provide compelling evidence supporting an overall favorable benefit-risk profile. We remain steadfast that this important treatment remain available to pediatric patients with SMA less than two years of age,” Novartis said in its statement. “At no time during the investigation did the findings indicate issues with product safety, efficacy or quality. We remain fully capable of releasing high-quality, fully compliant Zolgensma to patients in need.”

Zolgensma was approved in May as a treatment for children younger than two years old who have been diagnosed with SMA with bi-allelic mutations in the survival motor neuron 1 (SMN1) gene. SMA is a rare, genetic neuromuscular disease caused by a defective or missing SMN1gene. Infants with SMA lose the motor neurons responsible for muscle functions such as breathing, swallowing, speaking and walking. The disease can lead to death. Zolgensma is the first and only gene therapy approved by the FDA for the treatment of SMA, including those who are pre-symptomatic at diagnosis.

At the time of its approval, Novartis Chief Executive Officer Vas Narasimhan said the company believes Zolgensma will create a “lifetime of possibilities” for children who are eligible for the treatment. He also said the therapy will be “life-changing” for the patients, as well as their families.

While the FDA remains confident about the efficacy and safety of Zolgensma, which has a price tag of $2.1 million, the agency said AveXis became aware of the data manipulation issue prior to the FDA’s approval of the therapy. The FDA said it will “use its full authorities to take action” if necessary. That could include civil or criminal penalties, the agency said.

The FDA said it is conducting a “thorough assessment” of the information from a recently complete inspection of AveXis’ California manufacturing facility. The assessment will allow the FDA to review its own scientific review of the Zolgensma data from the BLA and provide the agency with an opportunity to make any necessary amendments.

Novartis said it does not anticipate the issues regarding the preclinical data manipulation to impact the timing of our ongoing Zolgensma regulatory filings.