Expanded access

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Expanded access or compassionate use is the use of an unapproved drug or medical device under special forms of investigational new drug applications (IND) or IDE application for devices, outside of a clinical trial, by people with serious or life-threatening conditions who do not meet the enrollment criteria for the clinical trial in progress.

Contents

These programs go under various names, including early access, special access, or managed access program, compassionate use, compassionate access, named-patient access, temporary authorization for use, cohort access, and pre-approval access. [1] [2] [3]

In general the person and their doctor must apply for access to the investigational product, the company has to choose to cooperate, and the medicine's regulatory agency needs to agree that the risks and possible benefits of the drug or device are understood well enough to determine if putting the person at risk has sufficient potential benefit. In some countries the government will pay for the drug or device, but in many countries the person must pay for the drug or device, as well as medical services necessary to receive it.

In the US, compassionate use started with the provision of investigational medicine to certain patients in the late 1970s, and a formal program was established in 1987 in response to HIV/AIDS patients requesting access to drugs in development. An important legal case was Abigail Alliance v. von Eschenbach , in which the Abigail Alliance, a group that advocates for access to investigational drugs for people who are terminally ill, tried to establish such access as a legal right. The Supreme Court declined to hear the case, effectively upholding previous cases that have maintained that there is not a constitutional right to unapproved medical products.

Programs

As of 2016, regulation of access to pharmaceuticals that were not approved for marketing was handled on a country by country basis, including in the European Union, where the European Medicines Agency issued guidelines for national regulatory agencies to follow. In the US, Europe, and the EU, no company could be compelled to provide a drug or device that it was developing. [1]

Companies sometimes provide drugs under these programs to people who were in clinical trials and who responded to the drug, after the clinical trial ends. [2] [3]

United States

In the US as of 2018, people could try obtain unapproved drugs or medical devices that were in development under specific conditions. [4] [5]

These conditions were: [5]

Drugs can be made available to individuals, small groups, or large groups. [5]

In the US, actual provision of the drug depends on the manufacturer's willingness to provide it, as well as the person's ability to pay for it; it is the company's decision whether to require payment or to provide the drug or device for free. [1] The manufacturer can only charge direct costs for individual INDs; it can add some but not all indirect costs for small group or larger expanded access programs. [6] To the extent that a doctor or clinic is required for use of the drug or device, they too may require payment. [1]

In some cases, it may be in the manufacturer's commercial interest to provide access under an EA program; this is a way, for example, for a company to make money before the drug or device is approved. Companies must provide data collected from people getting the drug or device under EA programs to the FDA annually; this data may be helpful with regard to getting the drug or device approved, or may be harmful, should unexpected adverse events occur. The manufacturer remains legally liable as well. If the manufacturer chooses to charge for the investigational product, that price influences later discussions about the price if the product is approved for marketing. [1]

State law

As of February 2019, 41 states have passed right-to-try laws that permit manufacturers to provide experimental medicines to terminally ill people without US FDA authorization. [7] Legal, medical, and bioethics scholars, including Jonathan Darrow and Arthur Caplan, have argued that these state laws have little practical significance because people can already obtain pre-approval access through the FDA's expanded access program, and because the FDA is generally not the limiting factor in obtaining pre-approval access. [8] [9]

Europe

In Europe, the European Medicines Agency issued guidelines that members may follow. Each country has its own regulations, and they vary. In the UK, for example, the program is called "early access to medicine scheme" or EAMS and was established in 2014. If a company that wants to provide a drug under EAMS, it must submit its Phase I data to the Medicines and Healthcare products Regulatory Agency and apply for what is called a "promising innovative medicine" (PIM) designation. If that designation is approved, the data is reviewed, if that review is positive, the National Health Service is obligated to pay for people who fit the criteria to have access to the drug. As of 2016, governments also paid for early access to drugs in Austria, Germany, Greece, and Spain. [1] Since 2021, France has a system of early and expanded access separated in two systems: AAC and AAP. [10]

Companies sometimes make use of expanded programs in Europe even after they receive EMA approval to market a drug, because drugs also must go through regulatory processes in each member state, and in some countries this process can take nearly a year; companies can start making sales earlier under these programs. [1]

Philippines

In the Philippines, the usage of unregistered drugs may be allowed through a doctor, a specialist, or health institution or society obtaining a specific compassionate use permit (CSP) from the country's Food and Drug Administration for the treatment of their terminally or seriously ill patients. The issuance of CSP is stated under Department of Health Administrative Order No. 4 of 1992. [11]

Those seeking CSP are required to provide the following information; estimated amount of the unregistered drug the patient, the "licensed drug/device establishment through which the unregistered drug may be procured", and "the names and address of the specialists qualified and authorized to use the product." A CSP may also be obtained for processed medical cannabis despite cannabis in general being illegal in the Philippines. [11] [12]

History

Medicinal cannabis farmed by the University of Mississippi for the government U.S. Government Medical Marijuana crop. University of Mississippi. Oxford.jpg
Medicinal cannabis farmed by the University of Mississippi for the government

In the US, one of the earliest expanded access programs was a compassionate use IND that was established in 1978, which allowed a limited number of people to use medical cannabis grown at the University of Mississippi, under the direction of Marijuana Research Project Director Dr. Mahmoud ElSohly. It is administered by the National Institute on Drug Abuse.[ citation needed ]

The program was started after Robert C. Randall brought a lawsuit (Randall v. U.S) [13] against the FDA, the Drug Enforcement Administration, the National Institute on Drug Abuse, the Department of Justice, and the Department of Health, Education & Welfare. Randall, who had glaucoma, had successfully used the Common Law doctrine of necessity to argue against criminal charges of marijuana cultivation that had been brought against him, because his use of cannabis was deemed a medical necessity (U.S. v. Randall). [13] On November 24, 1976, federal Judge James Washington ruled in his favor. [14] : 142  [15]

The settlement in Randall v. U.S. became the legal basis for the FDA's compassionate IND program. [13] People were only allowed to use cannabis under the program who had certain conditions, like glaucoma, known to be alleviated with cannabis. The scope was later expanded to include people with AIDS in the mid-1980s. At its peak, fifteen people received the drug. 43 people were approved for the program, but 28 of the people whose doctors completed the necessary paperwork never received any cannabis. [16] [14] The program stopped accepting new people in 1992 after public health authorities concluded there was no scientific value to it, and due to President George H. W. Bush administration's policies. As of 2011, four people continued to receive cannabis from the government under the program. [17]

The closure of the program during the height of the AIDS epidemic led to the formation of the medical cannabis movement in the United States, a movement which initially sought to provide cannabis for treating anorexia and wasting syndrome in people with AIDS. [18]

In November 2001 the Abigail Alliance for Better Access to Developmental Drugs was established by Frank Burroughs in memory of his daughter, Abigail. [19] The Alliance seeks broader availability of investigational drugs on behalf of people with terminal illnesses. It is best known for a legal case, which it lost, Abigail Alliance v. von Eschenbach , in which it was represented by the Washington Legal Foundation. On August 7, 2007, in an 8–2 ruling, the U.S. Court of Appeals for the District of Columbia Circuit reversed an earlier ruling in favor of the Alliance. [20] In 2008, the Supreme Court of the United States declined to hear their appeal. This decision left standing the appellate court decision that people who are terminal ill patients have no legal right to demand "a potentially toxic drug with no proven therapeutic benefit". [21]

In March 2014, Josh Hardy, a 7-year-old boy from Virginia, made national headlines that sparked a conversation on pediatric access to investigational drugs when his family's request for brincidofovir was declined by the drug manufacturer, Chimerix. [22] The company reversed its decision after pressure from cancer advocacy organizations, and Josh received the drug that saved his life. [23] [24] Hardy later passed away in September 2016 due to complications related to his underlying cancer diagnosis. [25] In 2016 Kids v Cancer, a pediatric cancer advocacy organization, launched the Compassionate Use Navigator to assist physicians and guide families about the application process. [26] Since then, FDA simplified the application process, but stressed that it cannot require a manufacturer to provide a product. [27] [28] FDA receives about 1,500 expanded access requests per year and authorizes 99% of it. [29]

See also

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<span class="mw-page-title-main">Cannabidiol</span> Phytocannabinoid discovered in 1940

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<span class="mw-page-title-main">New Drug Application</span> Request US FDA approve new medications

The Food and Drug Administration's (FDA) New Drug Application (NDA) is the vehicle in the United States through which drug sponsors formally propose that the FDA approve a new pharmaceutical for sale and marketing. Some 30% or less of initial drug candidates proceed through the entire multi-year process of drug development, concluding with an approved NDA, if successful.

<span class="mw-page-title-main">Investigational New Drug</span> USFDA permission to test

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<span class="mw-page-title-main">Off-label use</span> Use of pharmaceuticals for conditions different from that for which they were approved

Off-label use is the use of pharmaceutical drugs for an unapproved indication or in an unapproved age group, dosage, or route of administration. Both prescription drugs and over-the-counter drugs (OTCs) can be used in off-label ways, although most studies of off-label use focus on prescription drugs.

An adverse event (AE) is any untoward medical occurrence in a patient or clinical investigation subject administered a pharmaceutical product and which does not necessarily have a causal relationship with this treatment. An adverse event can therefore be any unfavourable and unintended sign, symptom, or disease temporally associated with the use of a medicinal (investigational) product, whether or not related to the medicinal (investigational) product.

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A glossary of terms used in clinical research.

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Right-to-try laws are United States state laws and a federal law that were created with the intent of allowing terminally ill patients access to experimental therapies that have completed Phase I testing but have not been approved by the Food and Drug Administration (FDA). Prior to the passage of right to try laws, patients needed FDA approval to use experimental drugs. As of 2018, 41 U.S. states had passed right to try laws. The framers of these laws argue that this allows for individualized treatments that are not permitted under the FDA's current regulatory scheme. The value of these laws was questioned on multiple grounds, including the fact that pharmaceutical manufacturers would have no obligation to provide the therapies being sought. A federal right to try law was passed in May 2018. Very little data is available about the number of patients who have used the right-to-try pathway, but available sources indicate that since the signing of the bill only a handful of patients have used this pathway to access experimental therapies, as most physicians and sponsors prefer the more traditional, FDA approved, Expanded Access route. According to Scott Gottlieb, who served as commissioner of the FDA under President Donald Trump, the FDA had already approved 99% of patient requests for access to experimental drugs, either immediately over the phone or within a few days, prior to the passage of right to try legislation.

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References

Citations

  1. 1 2 3 4 5 6 7 Patil, S (2016). "Early access programs: Benefits, challenges, and key considerations for successful implementation". Perspectives in Clinical Research. 7 (1): 4–8. doi: 10.4103/2229-3485.173779 . PMC   4763516 . PMID   26955570.
  2. 1 2 Balasubramanian, G.; Morampudi, S.; Chhabra, P.; Gowda, A.; Zomorodi, B. (2016), "An overview of Compassionate Use Programs in the European Union member states", Intractable & Rare Diseases Research, 5 (4): 244–254, doi:10.5582/irdr.2016.01054, PMC   5116859 , PMID   27904819
  3. 1 2 Hyry, HI; Manuel, J; Cox, TM; Roos, JC (21 August 2015). "Compassionate use of orphan drugs". Orphanet Journal of Rare Diseases. 10: 100. doi: 10.1186/s13023-015-0306-x . PMC   4546220 . PMID   26292942.
  4. ↑ "US National Cancer Institute – Access to Investigational Drugs". 17 April 2018.
  5. 1 2 3 "Expanded Access (Compassionate Use)". FDA. 27 April 2018. Retrieved 21 May 2018.
  6. ↑ Darrow, JJ; Sarpatwari, A; Avorn, J; Kesselheim, AS (15 January 2015). "Practical, legal, and ethical issues in expanded access to investigational drugs". The New England Journal of Medicine. 372 (3): 279–86. doi: 10.1056/NEJMhle1409465 . PMID   25587952.
  7. ↑ Darrow JJ; et al. (Jan 2015). "Practical, legal, and ethical issues in expanded access to investigational drugs". N Engl J Med. 372 (3): 279–86. doi: 10.1056/NEJMhle1409465 . PMID   25587952.
  8. ↑ Darrow, Jonathan J.; Sarpatwari, Ameet; Avorn, Jerry; Kesselheim, Aaron S. (2015). "Practical, Legal, and Ethical Issues in Expanded Access to Investigational Drugs". New England Journal of Medicine. 372 (3): 279–286. doi: 10.1056/NEJMhle1409465 . ISSN   0028-4793. PMID   25587952.
  9. ↑ Caplan, A (2016-01-16). "Medical Ethicist Arthur Caplan Explains Why He Opposes 'Right-to-Try' Laws". Oncology (Williston Park, N.Y.). 30 (1): 8. PMID   26791839.
  10. ↑ BOREL, Céline (2023-03-13). "Réforme de l'accès dérogatoire aux médicaments (MAJ 29/08/23)". OMEDIT Ile de France (in French). Retrieved 2023-12-19.
  11. 1 2 Viray, Patricia Lourdes (18 December 2018). "Fact check: Is medical marijuana already allowed in the Philippines?". The Philippine Star. Retrieved 24 December 2021.
  12. ↑ Cabal, Ruth (16 October 2017). "FDA : 'Compassionate permits' for imported cannabis-based drugs allowed, but no request yet". CNN Philippines. Archived from the original on October 19, 2017. Retrieved 24 December 2021.
  13. 1 2 3 Ben Amar M (2006). "Cannabinoids in medicine: a review of their therapeutic potential". Journal of Ethnopharmacology. 105 (1–2): 1–25. doi:10.1016/j.jep.2006.02.001. PMID   16540272.
  14. 1 2 Lee, Martin A. (August 2012). Smoke Signals: A Social History of Marijuana - Medical, Recreational and Scientific. Simon and Schuster. p. 234. ISBN   9781439102602.
  15. ↑ The Criminal Law Reporter. 20. Bureau of National Affairs. Arlington, Va. 1976. p. 2300.
  16. ↑ Rupnow, Chuck (August 9, 1997). "Painful journey: Woman aims to gain support for marijuana as medicine". Eau Claire Leader-Telegram .
  17. ↑ AP (September 27, 2011). "4 Americans get medical pot from the feds". Associated Press News.
  18. ↑ Werner, Clinton A. (June 2001). "Medical Marijuana and the AIDS Crisis". Journal of Cannabis Therapeutics. 1 (3–4): 17–33. doi:10.1300/J175v01n03_03.
  19. ↑ Phillips, Lisa (4 September 2008). "Contract Law and Ethical Issues Underscore the Latest Lawsuit About Access to Experimental Drugs for Duchenne Muscular Dystrophy". Neurology Today . 8 (17): 20. doi:10.1097/01.nt.0000337676.20893.50.
  20. ↑ "Your Weekly Update of News and Reviews". Consumer Health Digest (#07–30). 7 August 2007.
  21. ↑ "No right to experimental drugs for dying patients: Supreme Court". Agence France-Presse. 14 January 2008. Archived from the original on 5 March 2012. Retrieved 7 July 2013.
  22. ↑ Correspondent, By Elizabeth Cohen, Senior Medical. "Company denies drug to dying child - CNN". CNN. Retrieved 2018-07-06.{{cite news}}: CS1 maint: multiple names: authors list (link)
  23. ↑ "Saved Josh: The gears of a successful patient advocacy campaign (Case study, by Elena Gerasimov) | Kids v Cancer". www.kidsvcancer.org. Retrieved 2018-07-06.
  24. ↑ Catherine E. Shoichet; Elizabeth Cohen. "Drug company: Ailing 7-year-old Josh Hardy will get medicine". CNN. Retrieved 2018-07-06.
  25. ↑ "Josh Hardy, Va. Boy Who Inspired Social Media Campaign, Dies". NBC4 Washington. 22 October 2016. Archived from the original on 22 May 2018. Retrieved 2018-05-21.
  26. ↑ Gerasimov, Elena; Zhang, Lindy; Moerdler, Scott; Roth, Michael; Goodman, Nancy; Weiser, Daniel (2016-07-15). "Abstract LB-146: Compassionate use navigator addresses challenges and facilitates access to investigational drugs for pediatric oncologists". Cancer Research. 76 (14 Supplement): LB–146–LB–146. doi:10.1158/1538-7445.AM2016-LB-146. ISSN   0008-5472.
  27. ↑ "Expanded Access: FDA Describes Efforts to Ease Application Process | FDA Voice". blogs.fda.gov. Retrieved 2018-07-06.
  28. ↑ Frellick, Marcia (June 3, 2016). "FDA Simplifies Compassionate Use Application and Drug Costs". Medscape .
  29. ↑ "Expanded Access (Compassionate Use) - Expanded Access INDs and Protocols 2009 - 2017". FDA.gov. U.S. Food and Drug Administration. Archived from the original on 2018-05-17. Retrieved 2018-07-06.

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