Development of New Drugs in the US- An Update

Last week news of President Biden Plan on lowering drug prescription costs reminded me of my article about drug development in the US.

https://twitter.com/search?q=lower+cost+of+prescription+drugs&ref_src=twsrc%5Egoogle%7Ctwcamp%5Eserp%7Ctwgr%5Esearch

 

I wrote this article a decade ago today. I believe the contents of this article is still valid today except the costs and success rate.

Development of New Drugs in the United States Schematic

Image from medscape.com

As a retired FDA involved in the development of new drugs in the Division of Anti-Infective Drug Products, Office of New Drug Chemistry, I had often been asked by several of my blog readers to write a summary and an overview of new drug development in the US. I had been postponing it, because I thought the subject is confidential, but when I started browsing in the WEB today, I found several articles on the subject. I even found a Chemistry manufacturing supplement that I had approved several years ago. The letter of approval and the chemist review was printed in the Internet. However, the specifics of the supplement was erased in the approval letter as well as in the chemist review. The patent of the drug discussed had expired, so it is open to generic companies, otherwise the chemist review and letter of approval will never be made public. I am getting out of the subject, but let me start on the subject right now.

New Chemical Entity (NCE) development

Broadly the process can be divided into pre-clinical and clinical work.

Pre-clinical.

New Chemical Entities (NCEs)(also known as New Molecular Entities (NMEs)) are compounds which emerge from the process of drug discovery. These will have promising activity against a particular biological target thought to be important in disease; however, little will be known about the safety, toxicity, pharmacokinetics and metabolism of this NCE in humans. It is the function of drug development to assess all of these parameters prior to human clinical trials. A further major objective of drug development is to make a recommendation of the dose and schedule to be used the first time an NCE is used in a human clinical trial ("first-in-man" (FIM) or First Human Dose (FHD)).

In addition, drug development is required to establish the physicochemical properties of the NCE: its chemical makeup, stability, solubility. The process by which the chemical is made will be optimized so that from being made at the bench on a milligram scale by a synthetic chemist, it can be manufactured on the kilogram and then on the ton scale. It will be further examined for its suitability to be made into capsules, tablets, aeresol, intramuscular injectable, subcuteneous injectable, or intravenous formulations. Together these processes are known in preclinical development as Chemistry, Manufacturing and Control (CMC).

Note: The CMC portion of was my primary function as the Team Chemistry Leader during my employment with FDA

Many aspects of drug development are focused on satisfying the regulatory requirements of drug licensing authorities. These generally constitute a number of tests designed to determine the major toxicities of a novel compound prior to first use in man. It is a legal requirement that an assessment of major organ toxicity be performed (effects on the heart and lungs, brain, kidney, liver and digestive system), as well as effects on other parts of the body that might be affected by the drug (e.g. the skin if the new drug is to be delivered through the skin). While, increasingly, these tests can be made using in vitro methods (e.g. with isolated cells), many tests can only be made by using experimental animals, since it is only in an intact organism that the complex interplay of metabolism and drug exposure on toxicity can be examined.

The information gathered from this pre-clinical testing, as well as information on CMC, and is submitted to regulatory authorities (in the US, to the FDA), as an Investigational New Drug application or IND. If the IND is approved, development moves to the clinical phase.

Clinical phase.

Clinical trials involves three steps: Phase I trials, usually in healthy patients, determine safety and dosing Phase II trials are used to get an initial reading of efficacy and further explore safety in small numbers of sick patients Phase III trials a large, pivotal trials to determine safety and efficacy in sufficiently large numbers of patients

The process of drug development does not stop once an NCE begins human clinical trials. In addition to the tests required to move a novel drug into the clinic for the first time it is also important to ensure that long-term or chronic toxicities are determined, as well as effects on systems not previously monitored (fertility, reproduction, immune system, etc.). The compound will also be tested for its capability to cause cancer (carcinogenicity testing).

If a compound emerges from these tests with an acceptable toxicity and safety profile, and it can further be demonstrated to have the desired effect in clinical trials, then it can be submitted for marketing approval in the various countries where it will be sold. In the US, this process is called a New Drug Application or NDA. Most NCEs, however, fail during drug development, either because they have some unacceptable toxicity, or because they simply do not work in clinical trials.

As this drug discovery process becomes more expensive it is becoming important to look at new ways to bring forward NCEs. One approach to improve efficiency is to recognize that there are many steps requiring different levels of experimentation. The early phase of drug discovery actually has components of real innovation, components of experimentation and components that involve set routines. This model of Innovation, Experimentation, and Commoditization ensures that new ways to do work are adopted continually. This model also allows the discipline to use appropriate internal and external resources for the right work.

Costs

Studies published by diMasi et al in 2003 report an average pre-tax cost of approximately $800 million to bring a new drug (i.e. a drug with a new chemical entity) to market. A study published in 2006 estimates that costs vary from around $500 million to $2 billion depending on the therapy or the developing firm. A study published in 2010 in the journal Health Economics, including an author from the US Federal Trade Commission, was critical of the methods used by diMasi et al but came up with a higher estimate of ~$1.2B. Critic Marcia Angell, M.D., a former editor of the New England Journal of Medicine, has called that number grossly inflated, and estimates that the total is closer to $100 million. A 2011 study also critical of the diMasi methods, puts average costs at $55 million.

Success rate

Candidates for a new drug to treat a disease might theoretically include from 5,000 to 10,000 chemical compounds. On average about 250 of these will show sufficient promise for further evaluation using laboratory tests, mice and other test animals. Typically, about ten of these will qualify for tests on humans. A study conducted by the Tufts Center for the Study of Drug Development covering the 1980s and 1990s found that only 21.5 percent of drugs that start phase I trials are eventually approved for marketing. Now you know why the drugs you purchased in the pharmacy is very expensive ( except the generic drugs). Most Americans will not be able to afford new drugs if they do not have insurance.

The mission of FDA is to enforce laws enacted by the U.S. Congress and regulations established by the Agency to protect the consumer's health, safety, and pocketbook. The Federal Food, Drug, and Cosmetic Act20 is the basic food and drug law of the U.S. With numerous amendments it is the most extensive law of its kind in the world. The law is intended to assure consumers that foods are pure and wholesome, safe to eat, and produced under sanitary conditions; that drugs and devices are safe and effective for their intended uses; that cosmetics are safe and made from appropriate ingredients; and that all labeling and packaging is truthful, informative, and not deceptive.Code of Federal Regulations (CFR)

Code Of Federal Regulations (CFR)21. The final regulations published in the Federal Register22 (daily published record of proposed rules, final rules, meeting notices, etc.) are collected in the CFR. The CFR is divided into 50 titles that represent broad areas subject to Federal regulations. The FDA's portion of the CFR interprets the The Federal Food, Drug, and Cosmetic Act23 and related statutes. Section 21 of the CFR24 contains most regulations pertaining to food and drugs.

Note: I hope you found the above posting informative. My next posting on this subject will be on the Chemistry, Manufacturing and Control(CMC) Requirements for IND's and NDA's. If you find this posting either boring or interesting, let me know via comments. Thank You.

 Comment:

Anonymous said...You have a very informative article, I hope the FDA does not condone your site for writing about their business. Would you know how much the FDA charges drug companies for testing each of their new drugs from start to finish? This must cost them a bundle because, FDA employs a plethora of highly educated doctors, scientists, mathematicians and business people. Jeffrey Ray

A very interesting interview about the development of new drugs by Dan Skovronsky, Director of Research and Development, Eli Lily. 

 

Meanwhile enjoy this photo from my collection-My Pineapple in my front Patio almost ready to be harvested.

-

 

 

Childhood Dreams and the Afterglows of the Sunset of Our Lives for the StoryWorth Book

A. Dreams of Childhood- Accomplished and Partially Accomplished

The Japanese Bridge of Chateau Du Mer Beach Resort on Sunset, Boac, Marinduque, Philippines

When I was growing up in the small town of Barotac Viejo, Iloilo, Philippines in the mid 1940's, I had several dreams and goals in life. One of my first dream after seeing a movie made in US was to see and visit( not reside) US and play in the snow. This dream was attained in 1960. My other dream was to live in a house surrounded by fruit trees, flowers and orchids. This dream was realized in 1996 when we built our retirement home in Boac, Marinduque. Another dream I had was to build a Japanese bridge across a creek( see photo above) populated by tilapias and other fishes. This was attained when we constructed the beach house in 1998.

As a child I never dreamed to be rich in money, but just earned enough to live comfortably. This was fulfilled when we immigrated to US and after I completed my Ph.D degree in 1964. Completion of this graduate degree was the most important goal and dream in my life.

My last dream in my childhood years was to have a residence with a circular driveway with a fountain in the center. This dream was never attained completely. However, this dream, was partially fulfilled when we built the Chateau Du Mer Conference Hall in 2000. The Hall had a semi-circular driveway but no fountain. Building a fountain in the center was planned before construction. However, for practical reasons and lack of funds, this dream will probably not be fully realized unless I win a lot of $$ in the Lotto or at the Casinos.

Finally, I thank God for all his blessings for helping me attained most of my dreams and goals in life. Lord without YOU, I am nothing.

B.Afterglows in the Sunset of our Lives


The other day while looking at my old photo files, I found the above photograph. It is a sunset and its afterglow from the west balcony of our retirement beach house in Boac, Marinduque, Philippines taken ten years ago. Looking at the photo reminded me of both Macrine's and my professional life in the US.  Macrine retired as Manager, Quality Assurance Nurse Manager from one of Maryland's Home Health Nursing Company.  Macrine joined her Creator on August 10, 2020

I retired from FDA as a Chemistry Team Leader in the Center of New Drugs, Silver Spring, MD. Both of us had satisfying careers( I had received several awards, letters of commendation and appreciation, and an EEO award). So when we retired in the Fall of 2002, we often ask ourselves, if this is all that we can contribute to society and the community.

Since retirement is often called " the sunset of your life" stage, are there afterglows in our lives that we can be proud of. Yes, indeed! The following are examples of the afterglows in the sunset of our lives.

Several years ago, Macrine received a letter of Appreciation and Thanks from the late Governor Carmencita Reyes(RIP) because of her involvement in MI, Inc Medical Mission Of Love, 2006. Macrine was president and over-all chairperson of the medical mission in Marinduque that year. Here's an excerpt from C Reyes letter of Thanks.

Dear Mrs. Katague,

I would like to extend our heartfelt gratitude for all the assistance extended by MI, Inc. Your association is one of our full-time partners in the delivery of health services particularly in the conduct of medical/surgical missions which benefited hundreds of Marinduquenos. Thank you so much for the support and assistance extended to our administration and to the people of Marinduque. Mabuhay Kayo!

In addition about two decades ago, Macrine and I received a Letter of Thanks and Appreciation from then Governor Antonio Carrion in our efforts to promote tourism in the island not only during Easter but also whole year round. The letter mentioned several of my blogs and articles that proclaimed my love for the province and encouraging other Balikbayans to build retirement homes in the island.

In 2009, my dream as a "citizen journalist" was attained when two of my articles was accepted for publication in HULIQ News. The first article was about Marinduque as the Ecotourism capital of the Philippines. The second was on the revival of the Bataan Nuclear Power Plant in Morong, Bataan.

Last but not least: Just recently two of my thousands of readers of my seven blogs commented: " I have been reading your various blogs and websites for about one week now. They are all well written and great reading. What I have been reading and following intently in your blog is your life story, very interesting and inspiring indeed. Please keep on writing and thanks for opening yourself up in your blogs."

A second reader also commented: I have been following your blog for quite sometime. I learned a lot about Marinduque and the Philippines. I specially enjoyed reading your childhood experiences during the Japanese-American War. Your contribution as an FDA employee to the burnt victims of the bombing in New York and the Pentagon in 2011 is indeed commendable and worthy of an award. Keep writing!

Will there be more afterglows in the future? I hope so. I would like to hear that our oldest grandson ( now 30) got married and gave us a great grandchild. In addition, we would like to hear the news that our youngest granddaughter( now 18) had graduated from college and that I am still healthy to attend her graduation.

Final Word of Wisdom to all My Readers: Be Happy and Trust in the Lord!

 

Photo Memories of Chateau Du Mer and Bellarocca Resort in Marinduque

The Front Gate of Chateau Du Mer, 2010

 

Eleven years and six months ago, I took the following photographs of Chateau Du Mer (CDM)-our second home and vacation compound in Amoingon, Boac, Marinduque, Philippines when daily maintenance was routine.

One of the Many Orchids in the Gardens of Chateau Du Mer

Orchids Galore on Driveway from Main Road

Front Yard of the Main House

     

Driveway of the Main House and Servant Quarters

Front Porch of the Main House( there is a Back Porch Facing the Ocean)

Back Porch of Main House with Sea View

Living Room of Main House showing Marble Floor 

My Computer and Desk in Master Bedroom

Hand Carved Head Boards Locally Made

My Lucban Tree( Chinese Grapefruit)-one of more than a dozen fruit trees in the Compound

The Conference Hall-Available for Private Daily Rental

The Conference Hall-South View

Conference Hall-Front Decorated for Wedding Reception

The Beach House-At the Back of the Conference Hall

The Bridge over the Creek-Focal Point of the Beach House Landscaping

The Beach House-Seaside View( West)

Beach House Lower Level with Bunk Beds

*************************************************************************************************

The second set of photos were memories of our private tour ( with Annie Miles and Aquilana Rivas) of the Bellarocca Beach Resort and Spa in Buenavista, Marinduque. At that time the resort was rated 5 Star and one of the best in Asia.  https://asiangrandlegacy.com/portfolio-items/bellarocca-island-resort/

On Our Way to a Private Tour of Bellarocca ( Macrine and I with Annie Miles and Aquilina Rivas), Dec 28, 2010

Macrine enjoying the view of the Main land from one of the Rooms at the Resort

View of Mt Malindig from the Resort

Meanwhile, enjoy this video of Chateau Du Mer

https://youtu.be/qLr3m6WjvXw

Meanwhile enjoy this photo from my front yard this year

Orange Ice Plant in Front Yard of Residence- April, 2021

 

A Treasured Message from a FaceBook Friend

• Just recently, I received a message in FB from a former resident of the UP Mens South Dorm (Narra Hall) that I am posting below. His message reminded me of the many happy years I experienced in UP from 1952 to 1958. The following photos are reminders of my pleasant memories of those years UP Mens South Dorm Association, 1954. I am in the second row, 7th from the right. In this picture, I know of two politicians. One is Luis Villafuerte (second row, second from the right) former governor and assembly man from Camarines Sur. The other one is Homobono Adaza, former governor and assembly man from Misamis Oriental. Both were law students at that time. Villafuerte's dorm room was just across the Hall from mine. If you know any one in this picture, please let me know via FaceBook or in this blog.
  
  UP Men's South Dorm Officers, 1954. I am in the front row, first from the left with a notebook.
  
  Liberal Arts Chapter Members of the University of the Philippines Student Catholic Action (UPSCA) in front of the LA building in 1954
  
  Group Picture of some UPSCANS during our annual picnic outside the university campus, 1954 (Taal Vista Lodge).
  
  One More UPSCAN Picnic Picture, 1954
  
  During the Mens South Dorm Open House with Mercy Lopez, College of Music, Hector Taleon and my two room mates Vivencio Villaflor and Emmanuel Espino from Dagupan City, Pangasinan, 1954
  
  Me at the Analytical Laboratory.1954
  
  Weighing at the Analytical Balance Room,with Kahirup Juan, 1954
  
  Reading and relaxing in my room in the South Dorm after studying for 3 hours for a final exam in Physical Chemistry
  
  Bachelor of Science in Chemistry Graduation Photo, October, 1955.  

   

  Recently, I sent a Happy Birthday Greeting to GP ( a FB Friend and former resident of the UP Men's South Dorm in Diliman). The following was his response.
  

   

  FB Friend:
  

  This is so heartfelt. I couldn’t thank you enough.

  Lubos po ang aking kasiyahan na ako po ay binati ninyo. Ginagalang ko po kayo bilang isa sa orihinal na residente Ng UP South Men's Dormitory noong early 1950s na naging Mayon Residence Hall,

  at kalauna'y Narra kung saan ako sumilong Ng mahigit dalawang taon.

  • 
    
• 
  
David B Katague
Maraming Salamat. I hope all is well with You! Take Care!

FB Friend:

David B Katague Your version of shine is a search light. Thanks for lighting up the Narrehan path.The Earth is better off having you in it.
In this world there are 'drains' and 'radiators.' Drains take energy away while radiators beam it out. Continue being a radiator that continuously gives out warmth and comfort.

Again, a million thanks to GP. Your words are music to my aging years. May your tribe increase.  You have made MY DAY!!!

 

The Places We Have Visited Outside the US for the StoryWorth Book

The Butchart Gardens, Victoria, BC.- Look for Macrine in the Photo
 

This is my response to the query on the places we have visited outside the US for the StoryWorth Book of Memories. 

 

The places that we have visited outside the mainland US were Vancouver, Victoria, Ontario, British Columbia, Canada, London, Rome, Marbella, Spain, Tangiers, Morocco, Cancun, Mexico, San Juan, Puerto Rico, Aruba and Gibraltar and all the Hawaiian Islands. This was in relation to our International Interval Exchange Vacation Program.  Memorable memories, indeed!

 

One of the fifteen places that my wife and I have visited outside the US was our trip in August, 2005 to Vancouver, Victoria and Whistler, B.C., Canada. . This was in connection with another Grand Reunion of Marinduque International, Inc- a non-profit organization organized to give free medical missions to Marinduque, Philippines. It was one week of Fun and Relaxation that we will always remember.

 

British Columbia is on the western coast of Canada. The climate of Vancouver is Mediterranean similar to San Francisco, California. Vancouver is about 2 hours drive north of Seattle, Washington and has also a large Filipino-American community. We enjoyed Stanley Park, Queen Elizabeth(Sunken Garden) Park and Exotic China Town. Historic Gas Town and the drive along English Bay Drive was great. We took a sunset dinner cruise along Vancouver Harbor passing through English Bay, False Creek, Burrard Inlet and under the Lions Gate bridge(photos above).

We took a tour of Victoria, the capital city of British Columbia. The tour started from Vancouver via a 90-minute ferry ride across Georgia Strait and the beautiful Gulf Islands. Included in the tour is an admission to the world famous Butchart Garden (photo above). Here are two videos of the Butchart Gardens, one of the most beautiful gardens in the world.

The tour included a 30 minute drive along Beach Drive with views of Juan De Fuca strait and the Olympic Mountains. We also passed by the Upland and Oak Bay Streets residential areas, the Royal Victoria Yatch Club and the University of Victoria ending at the Victoria Harbor. Photo of Victoria Inner Harbor at Night-from thelifeofluxury.com

The next day, we took a one-day tour to Whistler, site of the 2010 Winter Olympics. The scenic tour started with a relaxing drive up the Sea to Sky Highway which overlooks majestic Howe Sound with its panorama of mountain lakes and glaciers. Along the way we stopped at Shannon Falls, one of North America's waterfalls at the Squamish Forest Reserve.

On our way to Whistler, Canada-Photo from www. people.uleth.ca

The second Place we have visited that we enjoyed very much is our vacation to Southern Spain ( Costa del Sol), Rock of Gibraltar and Tangiers, Morocco. 

  A Day in Tangiers in Morocco, North Africa

Camel Rides in Morocco

From Marbella,Spain, Macrine and I joined a one day tour to Tangier, Morocco, North Africa as part of our vacation in Costa del Sol in October, 2000. With this visit we could claim that we have been to the Continent of Africa. It was a beautifully organized tour and is described below by a writer from the Spanish tourism department:

"From the most southern point of Spain (Tarifa), Morocco is only 14 kilometers away. On most days you can see the mountains at the other side of the Strait of Gibraltar very clearly, and at night you see the lights of the houses. Being so close to Spain, Morocco Tourism is very tempting. Especially because it’s not only another country, but even another continent.

There are several options to a Morocco Tourism visit, one of them is booking a daytrip from Tarifa to Tangier( this is the one we took). There are two excursions to Tangier every day, starting at 9am and 11.00am, and cost 56 euro (ferry, guide, bus and lunch included). Tickets are sold at the office of FRS or at Marruecotur, both near the Paseo de la Alameda in the centre of Tarifa. The excursion starts in the port of Tarifa. Here you cross the Spanish border and get on the boat, a fast ferry that brings you in 35 minutes to Tangier. As there is a time difference between Morocco and Spain of 2 hours (in summer), you arrive in Morocco either around 7.45am or 9.45am.

"Once you have arrived in Morocco, a bus drives you from the port to the old town. The old town is surprisingly similar to a lot of old towns in Andalucian cities. At the entrance there is an old arc, after which you find a labyrinth of small streets, small houses, ancient buildings, a castle and small typical shops. Most of the shops appear to be there for tourists only, during the tour you’ll visit some of them. The shop owners are not too shy to sell you all their merchandise on the streets, of course for “a very special price” (which drops rapidly if you don’t show any interest). Also included in the tour is a lunch in a traditional Moroccan restaurant. They serve traditional food and at the end you’ll get a traditional Moroccan tea. It´s questionable if it´s really a traditional restaurant, as it seems to run on tourists only, but at least the food is good".

"After a stroll through the old town, you get a chance to have a look at the new town. This part of Tangier appears to be quite modern, with big buildings, broad streets and larger, more modern shops. A visit to the outskirts of Tangier is included as well. Big houses with big fences dominate the scene, so probably the rich are living here. You also get the opportunity to ride a camel, on payment of a few euros. The whole tour takes about 7 hours".

Personal Note: Walking on the narrow cobblestone streets of the Medina (Old Town) in Tangier was not easy. Street peddlers hustle you all day. They sell all kinds of trinkets that will challenge even an experienced bargain hunter like me. However, I had my good buy of the day on this tour. I saw a mineral stone ( similar to the one you see in the Smithsonian museum in Washington, DC) that aroused my attention. The asking price was 3000 pesetas. I bargained 500 pesetas. As expected I received a groaning response from the peddler( a man in his late 20's) that I am too cheap and should be ashamed for bargaining too low. I just smile and ignored him. The peddler keep up on following me until lunch time when the price went down to 2000 pesetas. I said no and stuck to my original bargain. I totally forgot about this haggling episode, when out of no where the peddler accosted me again and lowered the price to 1000 pesetas. I said no deal until the price went down to 700 pesetas. 

 

Three hours later as I was stepping on the bus on our way home, the peddler gave up. He gave the mineral stone to me as I handed him the 500 pesetas from the window of the bus. I certainly had a grand time in this haggling process. We did visit a carpet shop, but I was not in the mode of bargaining. In addition if we buy a carpet, it will be bulky to carry around, although they can shipped your purchase to the US with a ridiculously high fees.

Macrine on the other hand is not a bargain hunter or haggler. Her best purchase was what they called the "Moroccan Gold". It is the most expensive spice in the world.  It is SAFFRON. The powder looks light reddish brown, but when you add water it turns yellow, just like the color of TUMERIC, another spice. You need only a very small amount for cooking paella and other Spanish or Filipino dishes like the ginat-an na manok sa gata (chicken in coconut milk) of Marinduque-one of my favorite Filipino dish. Saffron is very expensive, so most cooks used a cheaper substitute, the TUMERIC or "dilaw" in Marinduque.


A snake Charmer in Action

I can not decide whether our # 3 place visited is our one week in Rome, Italy or in London UK. But for brevity I will post here only our Rome and surrounding areas vacation.  

 

Rome, the Vatican and Assisi and Vicinity, Italy

St Peter Square, The Vatican
On December 10 to 16, 1990, Macrine and I joined the Dioscese of Oakland Choir during their pilgrimage tour to Rome, the Vatican and surrounding area( Assisi), Italy. We were not members of the Choir, but our parish priest, Fr. Paddy Bishop of St Joseph Church of Pinole was the Chaperon of the Choir and he invited us to join the group. Lidia Carlos Reynes was the choir director. The choir gave one concert( liturgical music) and sang during a mass with the Pope (John Paul II) as celebrant in St Peter's Basilica. For 5 days we enjoyed the sights and sounds of Rome, the Vatican and Assisi, Italy.

One day we went to St Francis de Assisi Church in Assisi, Italy about one hour bus drive from Rome. Assisi is one of the most beautiful town in Italy. Around Rome, we saw the Coliseum, several the historic basilicas and fountains, the Catacombs and a whole day tour the Vatican( Sistine Chapel etc..)City and the Museum.
Assisi, Italy.
 

This is one vacation/tour that Macrine and I will never forget. The package tour was arranged by Courtial International, Vatican Travel Office and Choir Pilgrimage Services in Rome, Italy.
St Peter Square, the Vatican

The following paragraph in the concert program summarized the reason for this concert tour. ( there was a translation in Latin, German and French)

"Concerts of Liturgical Music in a Holy Place are not only authentic manifestations of Art and Faith, but they also represent a wonderful opportunity for the spirit to join the Source of every beauty".

I like the Spanish version better as follows:

"Los Conciertos de Musica Sagrada en Lugar Sagrado, ademas de ser autenticas manifestaciones de Arte y de Fe, constituyen una ocasion inmejorable para elevar al espiritu hacia la Fuente de la misma belleza."

Macrine and I at the Vatican Museum
 

Meanwhile enjoy Hauser's  rendition of Ave Maria (Schubert)

 

Binging On the Six Seasons of the TV Series- Downton Abbey

For the last two weeks, I have been binging on the TV Series- Downton Abbey. It reminded me of the old TV drama in the 1970's that I had enjoyed also Upstairs, Downstairs ( see below).  I binged Six Seasons in 10 days. Downton Abbey made me cry, laugh, meditate, and above all enjoy the drama and forgetting the long summer days staying at home due to Covid. In case you have not watched the series, here's some information from Wikipedia. I recommend it to all.

Downton Abbey is a British historical drama television series set in the early 20th century, created and co-written by Julian Fellowes. The series first aired on ITV in the United Kingdom on 26 September 2010, and in the United States on PBS, which supported production of the series as part of its Masterpiece Classic anthology, on 9 January 2011.

The series, set in the fictional Yorkshire country estate of Downton Abbey between 1912 and 1926, depicts the lives of the aristocratic Crawley family and their domestic servants in the post-Edwardian era—with the great events of the time having an effect on their lives and on the British social hierarchy. Events depicted throughout the series include news of the sinking of the Titanic in the first series; the outbreak of the First World War, the Spanish influenza pandemic, and the Marconi scandal in the second series; the Irish War of Independence leading to the formation of the Irish Free State in the third series; the Teapot Dome scandal in the fourth series; the British general election of 1923 and the Beer Hall Putsch in the fifth series. The sixth and final series introduces the rise of the working class during the interwar period and hints at the eventual decline of the British aristocracy.

Downton Abbey has received acclaim from television critics and won numerous accolades, including a Golden Globe Award for Best Miniseries or Television Film and a Primetime Emmy Award for Outstanding Miniseries or Movie. It was recognized by Guinness World Records as the most critically acclaimed English-language television series of 2011. It earned the most nominations of any international television series in the history of the Primetime Emmy Awards, with twenty-seven in total (after the first two series). It was the most watched television series on both ITV and PBS, and subsequently became the most successful British costume drama series since the 1981 television serial of Brideshead Revisited.

On 26 March 2015, Carnival Films and ITV announced that the sixth series would be the last. It aired on ITV between 20 September 2015 and 8 November 2015. The final episode, serving as the annual Christmas special, was broadcast on 25 December 2015. A film adaptation, serving as a continuation of the series, was confirmed on 13 July 2018 and subsequently released in the United Kingdom on 13 September 2019, and in the United States on 20 September 2019.

 

Upstairs, Downstairs is a British television drama series produced by London Weekend Television (LWT) for ITV. It ran for 68 episodes divided into five series on ITV from 1971 to 1975.

Set in a large townhouse in Belgravia in central London, the series depicts the servants—"downstairs"—and their masters, the family—"upstairs"—between the years 1903 and 1930, and shows the slow decline of the British aristocracy. Great events feature prominently in each episode but minor or gradual changes are also noted. The show stands as a document of the social and technological changes that occurred between those 27 years, including the Edwardian period, women's suffrage, the First World War, the Roaring Twenties, and the Wall Street Crash. It was a ratings success for ITV and received outstanding acclaim worldwide, winning multiple awards.

A BBC Wales and Masterpiece-produced continuation, Upstairs Downstairs, was broadcast by BBC One in 2010.

Meanwhile, enjoy this photo from my collection

Yuka, Ashley, Carenna and I playing Mahjong.